Oxabispidine compounds useful in the treatment of cardiac arrhythmias

ABSTRACT

There is provided compounds of formula I, 
                         
wherein R 1 , R 2 , R 3 , R 4 , R 41  to R 46 , A, B and G have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

This application is a divisional of application Ser. No. 10/317,195,filed Dec. 12, 2002 now U.S. Pat No. 7,164,017, which is a divisional ofapplication Ser. No. 09/688,251, filed Oct. 16, 2000 now U.S. Pat. No.6,559,143, the entire content of which is hereby incorporated byreference in this application.

FIELD OF THE INVENTION

This invention relates to novel pharmaceutically useful compounds, inparticular compounds which are useful in the treatment of cardiacarrhythmias.

BACKGROUND AND PRIOR ART

Cardiac arrhythmias may be defined as abnormalities in the rate,regularity, or site of origin of the cardiac impulse or as disturbancesin conduction which causes an abnormal sequence of activation.Arrhythmias may be classified clinically by means of the presumed siteof origin (i.e. as supraventricular, including atrial andatrioventricular, arrhythmias and ventricular arrhythmias) and/or bymeans of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias(fast)).

In the treatment of cardiac arrhythmias, the negative outcome inclinical trials (see, for example, the outcome of the Cardiac ArrhythmiaSuppression Trial (CAST) reported in New England. Journal of Medicine,321, 406 (1989)) with “traditional” antiarrhythmic drugs, which actprimarily by slowing the conduction velocity (class I antiarrhythmicdrugs), has prompted drug development towards compounds whichselectively delay cardiac repolarization, thus prolonging the QTinterval. Class III antiarrhythmic drugs may be defined as drugs whichprolong the trans-membrane action potential duration (which can becaused by a block of outward K⁺ currents or from an increase of inwardion currents) and refractoriness, without affecting cardiac conduction.

One of the key disadvantages of hitherto known drugs which act bydelaying repolarization (class III or otherwise) is that they all areknown to exhibit a unique form of proarrhythmia known as torsades depointes (turning of points), which may, on occasion be fatal. From thepoint of view of safety, the minimisation of this phenomenon (which hasalso been shown to be exhibited as a result of administration ofnon-cardiac drugs such as phenothiazines, tricyclic antidepressants,antihistamines and antibiotics) is a key problem to be solved in theprovision of effective antiarrhythmic drugs.

Antiarrhythmic drugs based onbispidines(3,7-diazabicyclo[3.3.1]nonanes), are known from inter aliainternational patent applications WO 91/07405 and WO 99/31100, Europeanpatent applications 306 871, 308 843 and 655 228 and U.S. Pat. Nos.3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well asjournal articles including inter alia J. Med. Chem. 39, 2559, (1996),Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal.Sci. 9, 429, (1993). Oxabispidine compounds are neither disclosed norsuggested in any of these documents.

Certain oxabispidine compounds are disclosed as chemical curiosities inChem. Ber., 96, 2872 (1963). That these compounds may be used in thetreatment of arrhythmias is neither mentioned nor suggested.

We have surprisingly found that a novel group of oxabispidine-basedcompounds exhibit electrophysiological activity, preferably class IIIelectrophysiological activity, and are therefore expected to be usefulin the treatment of cardiac arrhythmias.

DISCLOSURE OF THE INVENTION

According to the invention there is provided compounds of formula I,

wherein

-   R¹ represents C₁₋₁₂ alkyl (which alkyl group is optionally    substituted and/or terminated by one or more groups selected from    halo, cyano, nitro, aryl, Het¹, —C(O)R^(5a), OR^(5b), —N(R⁶)R^(5c),    —C(O)XR⁷, —C(O)N(R⁸)R^(5d), and —S(O)₂R⁹), or R¹ represents    —C(O)XR⁷, —C(O)N(R⁸)R^(5d) or —S(O)₂R⁹;-   R^(5a) to R^(5d) independently represent, at each occurrence, H,    C₁₋₆ alkyl (which latter group is optionally substituted and/or    terminated by one or more substituents selected from —OH, halo,    cyano, nitro, aryl and Het²), aryl or Het³, or R^(5d), together with    R⁸, represents C₃₋₆ alkylene (which alkylene group is optionally    interrupted by an O atom and/or is optionally substituted by one or    more C₁₋₃ alkyl groups);-   R⁶ represents H, C₁₋₆ alkyl (optionally substituted and/or    terminated by one or more substituents selected from —OH, halo,    cyano, nitro and aryl), aryl, —C(O)R^(10a), —C(O)OR^(10b) or    —C(O)N(H)R^(10c);-   R^(10a), R^(10b) and R^(10c) independently represent C₁₋₆ alkyl    (optionally substituted and/or terminated by one or more    substituents selected from —OH, halo, cyano, nitro and aryl), aryl,    or R^(10a) represents H;-   R⁷ represents C₁₋₁₂ alkyl (optionally substituted and/or terminated    by one or more substituents selected from —OH, halo, cyano, nitro,    aryl, C₁₋₆ alkoxy and Het⁴);-   R⁸ represents H, C₁₋₁₂ alkyl, C₁₋₆ alkoxy (which latter two groups    are optionally substituted and/or terminated by one or more    substituents selected from —OH, halo, cyano, nitro, C₁₋₄ alkyl and    C₁₋₄ alkoxy), -D-aryl, -D-aryloxy, -D-Het⁵, -D-N(H)C(O)R^(11a),    -D-S(O)₂R^(12a), -D-C(O)R^(11b), -D-C(O)OR^(12b),    -D-C(O)N(R^(11c))R^(11d), or R⁸, together with R^(5d), represents    C₃₋₆ alkylene (which alkylene group is optionally interrupted by an    O atom and/or is optionally substituted by one or more C₁₋₃ alkyl    groups);-   R^(11a) to R^(11d) independently represent H, C₁₋₆ alkyl (optionally    substituted and/or terminated by one or more substituents selected    from —OH, halo, cyano, nitro and aryl), aryl, or R^(11c) and R^(11d)    together represent C₃₋₆ alkylene;-   R⁹, R^(12a) and R^(12b) independently represent C₁₋₆ alkyl    (optionally substituted and/or terminated by one or more    substituents selected from —OH, halo, cyano, nitro and aryl) or    aryl;-   D represents a direct bond or C₁₋₆ alkylene;-   X represents O or S;-   R² represents H, halo, C₁₋₆ alkyl —OR¹³, -E-N(R¹⁴)R¹⁵ or, together    with R³, represents ═O;-   R³ represents H, C₁₋₆ alkyl or, together with R², represents ═O;-   R¹³ represents H, C₁₋₆ alkyl, -E-aryl, -E-Het⁶, —C(O)R^(16a),    —C(O)OR^(16b) or —C(O)N(R^(17a))R^(17b);-   R¹⁴ represents H, C₁₋₆ alkyl, -E-aryl, -E-Het⁶, —C(O)R^(16a),    —C(O)OR^(16b), —S(O)₂R^(16c), —[C(O)]_(p)N(R^(17a))R^(17b) or    —C(NH)NH₂;-   R¹⁵ represents H, C₁₋₆ alkyl, -E-aryl or —C(O)R^(16d);-   R^(16a) to R^(16d) independently represent, at each occurrence when    used herein,-   C₁₋₆ alkyl (optionally substituted and/or terminated by one or more    substituents selected from halo, aryl and Het⁷), aryl, Het⁸, or    R^(16a) and R^(16d) independently represent H;-   R^(17a) and R^(17b) independently represent, at each occurrence when    used herein, H or C₁₋₆ alkyl (optionally substituted and/or    terminated by one or more substituents selected from halo, aryl and    Het⁹), aryl, Het¹⁰, or together represent C₃₋₆ alkylene, optionally    interrupted by an O atom;-   E represents, at each occurrence when used herein, a direct bond or    C₁₋₄ alkylene;-   p represents 1 or 2;-   Het¹ to Het¹⁰ independently represent five- to twelve-membered    heterocyclic groups containing one or more heteroatoms selected from    oxygen, nitrogen and/or sulfur, which groups are optionally    substituted by one or more substituents selected from —OH, oxo,    halo, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl, aryloxy,    —N(R^(18a))R^(18b), —C(O)R^(18c), —C(O)OR^(18d),    —C(O)N(R^(18e))R^(18f), —N(R^(18g))C(O)R^(18h) and    —N(R^(18i))S(O)₂R^(18j);-   R^(18a) to R^(18j) independently represent C₁₋₆ alkyl, aryl or    R^(18a) to R^(18i) independently represent H;-   A represents a direct bond, -J-, -J-N(R¹⁹)— or -J-O— (in which    latter two groups, N(R¹⁹)— or O— is attached to the carbon atom    bearing R² and R³);-   B represents —Z—, —Z—N(R²⁰)—, —N(R²⁰)—Z—, —Z—S(O)_(n)—, —Z—O— (in    which latter two groups, Z is attached to the carbon atom bearing R²    and R³), —N(R²⁰)C(O)O—Z—, (in which latter group, —N(R²⁰) is    attached to the carbon atom bearing R² and R³) or —C(O)N(R²⁰)— (in    which latter group, —C(O) is attached to the carbon atom bearing R²    and R³);-   J represents C₁₋₆ alkylene optionally substituted by one or more    substituents selected from —OH, halo and amino;-   Z represents a direct bond or C₁₋₄ alkylene;-   n represents 0, 1 or 2;-   R¹⁹ and R²⁰ independently represent H or C₁₋₆ alkyl;-   G represents CH or N;-   R⁴ represents one or more optional substituents selected from —OH,    cyano, halo, nitro, C₁₋₆ alkyl (optionally terminated by    —N(H)C(O)OR^(21a)), C₁₋₆ alkoxy, —N(R^(22a))R^(22b), C(O)R^(22c),    —C(O)OR^(22d), —C(O)N(R^(22e))R^(22f), —N(R^(22g))C(O)R^(22h),    —N(R^(22i))C(O)N(R^(22j))R^(22k), —N(R^(22m))S(O)₂R^(21b),    —S(O)₂R^(21c), and/or —OS(O)₂R^(21d);-   R^(21a) to R^(21d) independently represent C₁₋₆alkyl;-   R^(22a) and R^(22b) independently represent H, C₁₋₆ alkyl or    together represent C₃₋₆ alkylene, resulting in a four- to    seven-membered nitrogen-containing ring;-   R^(22c) to R^(22m) independently represent H or C₁₋₆ alkyl; and-   R⁴¹ to R⁴⁶ independently represent H or C₁₋₃ alkyl;    wherein each aryl and aryloxy group, unless otherwise specified, is    optionally substituted;    provided that-   (a) the compound is not:    -   3,7-dibenzoyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;-   (b) when A represents -J-N(R¹⁹)— or -J-O—, then:    -   (i) J does not represent C₁, alkylene; and    -   (ii) B does not represent —N(R²⁰)—, —N(R²⁰)Z— (in which latter        group N(R²⁰) is attached to the carbon atom bearing R² and R³),        —S(O)_(n)—, —O— or —N(R²⁰)C(O)O—Z— when R² and R³ do not        together represent ═O; and-   (c) when R² represents —OR¹³ or —N(R¹⁴)(R¹⁵), then:    -   (i) A does not represent -J-N(R¹⁹)— or -J-O—; and    -   (ii) B does not represent —N(R²⁰)—, —N(R²⁰)—Z— (in which latter        group N(R²⁰) is attached to the carbon atom bearing R² and R³),        —S(O)_(n)—, —O— or —N(R²⁰)C(O)O—Z—;        or a pharmaceutically acceptable derivative thereof;        which compounds are referred to hereinafter as “the compounds of        the invention”.

Unless otherwise specified, alkyl groups and alkoxy groups as definedherein may be straight-chain or, when there is a sufficient number (i.e.a minimum of three) of carbon atoms be branched-chain, and/or cyclic.Further, when there is a sufficient number (i.e. a minimum of four) ofcarbon atoms, such alkyl and alkoxy groups may also be partcyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or,when there is a sufficient number (i.e. a minimum of two) of carbonatoms, be unsaturated and/or interrupted by one or more oxygen and/orsulfur atoms. Unless otherwise specified, alkyl and alkoxy groups mayalso be substituted by one or more halo, and especially fluoro, atoms.

Unless otherwise specified, alkylene groups as defined herein may bestraight-chain or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be branched-chain. Such alkylene chains may alsobe saturated or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be unsaturated and/or interrupted by one or moreoxygen and/or sulfur atoms. Unless otherwise specified, alkylene groupsmay also be substituted by one or more halo atoms.

The term “aryl”, when used herein, includes C₆₋₁₀ aryl groups such asphenyl, naphthyl and the like. The term “aryloxy”, when used hereinincludes C₆₋₁₀ aryloxy groups such as phenoxy, naphthoxy and the like.For the avoidance of doubt, aryloxy groups referred to herein areattached to the rest of the molecule via the O-atom of the oxy-group.Unless otherwise specified, aryl and aryloxy groups may be substitutedby one or more substituents including —OH, halo, cyano, nitro, C₁₋₆alkyl, C₁₋₆ alkoxy, —N(R^(22a))R^(22b), —C(O)R^(22c), —C(O)OR^(22d),—C(O)N(R^(22e))R^(22f), —N(R^(22g))C(O)R^(22h), —N(R^(22m))S(O)₂R^(21b),S(O)₂R^(21c), and/or —OS(O)₂R^(21d) (wherein R^(21b) to R^(21d) andR^(22a) to R^(22m) are as hereinbefore defined). When substituted, aryland aryloxy groups are preferably substituted by between one and threesubstitutents.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo.

Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸, Het⁹ and Het¹⁰)groups that may be mentioned include those containing 1 to 4 heteroatoms(selected from the group oxygen, nitrogen and/or sulfur) and in whichthe total number of atoms in the ring system are between five andtwelve. Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸, Het⁹ andHet¹⁰) groups may be fully saturated, wholly aromatic, partly aromaticand/or bicyclic in character. Heterocyclic groups that may be mentionedinclude benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl,benzimidazolyl, benzomorpholinyl, benzoxazinonyl, benzothiophenyl,chromanyl, cinnolinyl, dioxanyl, furanyl, imidazolyl,imidazo[1,2-α]pyridinyl, indolyl, isoquinolinyl, isoxazolyl,morpholinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimindinyl, pyrrolidinonyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thienyl, thiochromanyl,triazolyl and the like. Values of Het¹ that may be mentioned includepyridinyl, benzodioxanyl, imidazolyl, imidazo[1,2-α]pyridinyl,piperazinyl, pyrazolyl, pyrrolyl, pyrrolidinyl, tetrahydropyranyl andthiazolyl. Values of Het³ that may be mentioned include benzodioxanyland benzomorpholinyl. Values of Het⁴ that may be mentioned includepiperazinyl. Substituents on Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶,Het⁷, Het⁸, Het⁹ and Het¹⁰) groups may, where appropriate, be located onany atom in the ring system including a heteroatom. The point ofattachment of Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸, Het⁹and Het¹⁰) groups may be via any atom in the ring system including(where appropriate) a heteroatom, or an atom on any fused carbocyclicring that may be present as part of the ring system. Het (Het¹, Het²,Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸, Het⁹ and Het¹⁰) groups may also bein the N- or S-oxidised form.

Pharmaceutically acceptable derivatives include salts and solvates.Salts which may be mentioned include acid addition salts. Specific saltsthat may be mentioned include arylsulfonate salts, such astoluenesulfonate and, especially, benzenesulfonate salts. Solvates thatmay be mentioned include hydrates, such as monohydrates of the compoundsof the invention.

Pharmaceutically acceptable derivatives also include, at theoxabispidine or (when G represents N) pyridyl nitrogens, C₁₋₄ alkylquaternary ammonium salts and N-oxides, provided that when a N-oxide ispresent:

-   (a) no Het (Het¹, Het², Het³, Het⁴, Het⁵, Het⁶, Het⁷, Het⁸, Het⁹ and    Het¹⁰) group contains an unoxidised S-atom; and/or-   (b) n does not represent 0 when B represents —Z—S(O)_(n)—.

The compounds of the invention may exhibit tautomerism. All tautomericforms and mixtures thereof are included within the scope of theinvention.

The compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation, or by derivatisation, for example with a homochiral acidfollowed by separation of the diastereomeric esters by conventionalmeans (e.g. HPLC, chromatography over silica). All stereoisomers areincluded within the scope of the invention.

Abbreviations are listed at the end of this specification.

Compounds of formula I that may be mentioned include those in which,when R² and R³ together represent ═O, then A and B do not simultaneouslyrepresent direct bonds.

Preferred compounds of the invention include those in which:

-   R¹ represents C₁₋₈ alkyl (which alkyl group is optionally    substituted and/or terminated by one or more groups selected from    halo, optionally substituted aryl, optionally substituted Het¹,    —C(O)R^(5a), —OR^(5b), —N(R⁶)R^(5c), —C(O)N(R⁸)R^(5d), and    —S(O)₂R⁹), or R¹ represents —C(O)OR⁷, —C(O)N(R⁸)R^(5d) or —S(O)₂R⁹;-   R^(5a) to R^(5d) independently represent, at each occurrence, H,    C₁₋₆ alkyl (which latter group is optionally substituted and/or    terminated by one or more substituents selected from halo, cyano,    nitro and aryl), aryl (which latter group is optionally substituted    by one or more substituents selected from halo, hydroxy, cyano,    nitro, N(R^(22a))R^(22b) (in which latter group R^(22a) and R^(22b)    together represent C₃₋₆ alkylene), C₁₋₄ alkyl and C₁₋₄ alkoxy (which    latter two groups are optionally substituted by one or more halo    atoms)), Het³, or R^(5d), together with R⁸, represents C₄₋₅ alkylene    (which alkylene group is optionally interrupted by an O atom);-   R⁶ represents H, C₁₋₆ alkyl, aryl (which latter group is optionally    substituted by one or more substituents selected from halo, cyano,    nitro, C₁₋₄ alkyl and C₁₋₄ alkoxy), —C(O)R^(10a), —C(O)OR^(10b) or    C(O)N(H)R^(10c);-   R^(10a) and R^(10b) independently represent C₁₋₄ alkyl (optionally    substituted by one or more substituents selected from halo and aryl)    or aryl (which latter group is optionally substituted by or more    substituents selected from halo, cyano, nitro. C₁₋₄ alkyl and C₁₋₄    alkoxy);-   R^(10c) represents C₁₋₄ alkyl;-   R⁷ represents C₁₋₆ alkyl optionally substituted and/or terminated by    one or more substituents selected from halo, aryl, C₁₋₄ alkoxy and    Het⁴;-   R⁸ represents H, C₁₋₆ alkyl (which latter group is optionally    substituted and/or terminated by one or more substituents selected    from halo, cyano and nitro), -D-aryl, -D-aryloxy, -D-Het⁵,    -D-N(H)C(O)R^(11a), -D-C(O)R^(11b), or R⁸, together with R^(5d),    represents C₄₋₅ alkylene (which alkylene group is optionally    interrupted by an O atom);-   R^(11a) and R^(11b) independently represent C₁₋₄ alkyl (optionally    substituted and/or terminated by one or more substituents selected    from halo, cyano, nitro and aryl) or aryl;-   D represents a direct bond or C₁₋₃ alkylene;-   R⁹ represents C₁₋₆ alkyl (optionally substituted by one or more halo    groups) or aryl (which latter group is optionally substituted by one    or more substituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halo,    nitro and cyano);-   R² represents H, halo, C₁₋₃ alkyl, —OR¹³, —N(H)R¹⁴ or, together with    R³, represents ═O;-   R³ represents H, C₁₋₃ alkyl or, together with R², represents ═O;-   R¹³ represents H, C₁₋₄ alkyl, -E-aryl (optionally substituted by one    or more substituents selected from cyano, halo, nitro, C₁₋₄ alkyl    and C₁₋₄ alkoxy), or -E-Het⁶;-   R¹⁴ represents H, C₁₋₆ alkyl, -E-aryl (which aryl group is    optionally substituted by one or more substituents selected from    cyano, halo, nitro, C₁₋₄ alkyl and C₁₋₄ alkoxy), —C(O)R^(16a),    —C(O)OR^(16b), —S(O)₂R^(16c), —C(O)N(R^(17a))R^(17b) or —C(NH)NH₂;-   R^(16a) to R^(16e) independently represent C₁₋₆ alkyl, or R^(16a)    represents H;-   R^(17a) and R^(17b) independently represent H or C₁₋₄ alkyl;-   E represents a direct bond or C₁₋₂ alkylene;-   Het¹ to Het⁶ are optionally substituted by one or more substituents    selected from oxo, halo, cyano, nitro, C₁₋₄ alkyl, C₁₋₄ alkoxy,    —N(R^(18a))R^(18b), —C(O)R^(18c) or —C(O)OR^(18d);-   R^(18a) to R^(18d) independently represent H, C₁₋₄ alkyl or aryl;-   A represents -J-, -J-N(R¹⁹)— or -J-O—;-   B represents —Z—, —Z—N(R²⁰)—, —N(R²⁰)—Z—, —Z—S(O)_(n)—, —Z—O— or    —N(R²⁰)C(O)O—Z—;-   J represents C₁₋₄ alkylene;-   Z represents a direct bond or C₁₋₃ alkylene;-   n represents 0 or 2;-   R¹⁹ and R²⁰ independently represent H or C₁₋₄ alkyl;-   when G represents N, G is in the ortho- or, in particular, the    para-position relative to the point of attachment of B;-   when G represents N, R⁴ is absent or represents a single cyano    group;-   R⁴ is selected from —OH, cyano, halo, nitro, C₁₋₆ alkyl, C₁₋₆    alkoxy, —C(O)N(R^(22e))R^(22f), —N(R^(22g))C(O)R^(22h), and/or    —N(R^(22m))S(O)₂—C₁₋₄ alkyl;-   R^(22e) to R^(22m) independently represent H or C₁₋₄ alkyl;-   R⁴¹ to R⁴⁶ independently represent H.

More preferred-compounds of the invention include those in which:

-   R¹ represents straight-chain or branched-chain or part    cyclic/acyclic C₁₋₆ alkyl optionally interrupted by oxygen and/or    optionally substituted and/or terminated by: (i) one or more halo or    —OR^(5b) groups; and/or (ii) one group selected from phenyl (which    latter group is optionally substituted by one or more substituents    selected from halo, cyano and C₁₋₄ alkoxy (which latter group is    optionally substituted by one or more halo atoms)), Het¹,    —C(O)R^(5a), —N(H)R⁶, —C(O)N(R⁸)R^(5d), and —S(O)₂—C₁₋₄ alkyl, or R¹    represents —C(O)OR⁷, —C(O)N(R⁸)R^(5d) or —S(O)₂—C₁₋₅ alkyl;-   Het¹ represents a four- (e.g. five-) to ten-membered heterocyclic    group containing one or two heteroatoms selected from oxygen,    nitrogen and/or sulfur, which group is optionally substituted by one    or more substituents selected from C₁₋₂ alkyl and —C(O)—C₁₋₄ alkyl;-   R^(5a), R^(5b) and R^(5d) independently represent H, C₁₋₅ alkyl,    phenyl (which latter group is optionally substituted by one or more    substituents selected from halo, hydroxy, cyano, pyrrolidinyl, C₁₋₄    alkyl and C₁₋₅ alkoxy (which latter group is optionally substituted    by one or more halo atoms)) or Het³;-   Het³ represents a five- to ten-membered heterocyclic group    containing one or two heteroatoms selected from oxygen and nitrogen,    which group is optionally substituted by one or more substituents    selected from oxo, C₁₋₂ alkyl and —C(O)—C₁₋₄ alkyl;-   R⁶ represents H, C₁₋₄ alkyl, phenyl (which latter group is    optionally substituted by one or more cyano groups) or —C(O)O—C₁₋₅    alkyl;-   R⁷ represents C₁₋₅ alkyl optionally substituted or terminated by    Het⁴;-   Het⁴ represents a five- to ten-membered heterocyclic group    containing one or two heteroatoms selected from oxygen and nitrogen,    which group is optionally substituted by one or more substituents    selected from C₁₋₂ alkyl and —C(O)—C₁₋₄-alkyl;-   R⁸ represents H or C₁₋₄ alkyl;-   R² represents H, —OR¹³ or —N(H)R¹⁴;-   R³ represents H;-   R¹³ represents H or phenyl (optionally substituted by one or more    substituents selected from cyano and C₁₋₂ alkoxy);-   R¹⁴ represents H, phenyl (optionally substituted by one or more    cyano groups) or —C(O)O—C₁₋₅ alkyl;-   A represents C₁₋₃ alkylene;-   B represents —Z—, —Z—N(H)—, —Z—S(O)₂—, or —Z—O— (in which latter    three groups, Z is attached to the carbon atom bearing R² and R³);-   Z represents a direct bond or C₁₋₂ alkylene;-   G represents CH;-   R⁴ represents one or two cyano groups in the ortho- and/or, in    particular, the para-position relative to B.

Particularly preferred compounds of the invention include those inwhich:

-   R¹ represents straight-chain or branched-chain or part    cyclic/acyclic C₁₋₆ alkyl optionally interrupted by oxygen and/or    optionally substituted and/or terminated by: (i) one or more halo or    —OR^(5b) groups; and/or (ii) one group selected from phenyl (which    latter group is optionally substituted by one or more substituents    selected from halo, cyano and C₁₋₄ alkoxy (which latter group is    optionally substituted by one or more halo atoms)), Het¹,    —C(O)R^(5a), —N(H)R⁶, —C(O)N(R⁸)R^(5d), and —S(O)₂—C₁₋₄ alkyl.

Especially preferred compounds of the invention include those in which:

-   R¹ represents straight- or branched-chain C₁₋₄ alkyl (e.g. C₁₋₃    alkyl) terminated by —C(O)R^(5a) or —N(H)C(O)OR^(10b);-   R^(5a) and R^(10b) independently represent straight- or    branched-chain C₂₋₆ alkyl (e.g. C₃₋₅ alkyl, such butyl (e.g.    t-butyl));-   R² represents H or OH;-   A represents C₁₋₂ alkylene;-   B represents —Z—, —Z—N(H)— or —Z—O— (in which latter two groups, Z    is attached to the carbon atom bearing R² and R³, and represents    C₁₋₂ alkylene);-   R⁴ is a single cyano group in the para-position relative to B.

Preferred compounds of the invention include the compounds of theExamples disclosed hereinafter.

Preferred compounds of the invention also include those in which:

-   R⁶ does not represent —C(O)N(H)R^(10c);-   R^(22a) and R^(22b) do not together represent C₃₋₆ alkylene.

Preferred compounds of the invention also include those which are not:tert-butyl 7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;or ethyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;

Preparation

According to the invention there is also provided a process for thepreparation of compounds of formula I which comprises:

-   (a) reaction of a compound of formula II,

wherein R², R³, R⁴, R⁴¹ to R⁴⁶, A, B and G are as hereinbefore defined,with a compound of formula III,R¹-L¹  IIIwherein L¹ represents a leaving group such as halo, alkanesulfonate,perfluoroalkanesulfonate, arenesulfonate, —OC(O)XR⁷, imidazole or R²³O—(wherein R²³ represents, for example, C₁₋₁₀ alkyl or aryl, which groupsare optionally substituted by one or more halo or nitro groups) and X,R¹ and R⁷ are as hereinbefore defined, for example at between room andreflux temperature in the presence of a suitable base (e.g.triethylamine, potassium carbonate or a bicarbonate, such as sodiumbicarbonate) and an appropriate solvent (e.g. dichloromethane,chloroform, acetonitrile, N,N-dimethylformamide, THF, toluene, water, alower alkyl alcohol (e.g. ethanol) or mixtures thereof);

-   (b) for compounds of formula I in which R¹ represents —C(O)XR⁷ or    —C(O)N(R⁸)R^(5d), reaction of a compound of formula IV,

wherein R², R³, R⁴, R⁴¹ to R⁴⁶, A, B, G and L¹ are as hereinbeforedefined, with a compound of formula V,R²⁴—H  Vwherein R²⁴ represents —XR⁷ or —N(R⁸)R^(5d) and R^(5d), R⁷, R⁸ and X areas hereinbefore defined, for example under similar conditions to thosedescribed hereinbefore (process step (a));

-   (c) for compounds in which R¹ represents —C(O)N(H)R⁸, reaction of a    compound of formula II, as hereinbefore defined, with a compound of    formula VI,    R⁸—N═C═O  VI    wherein R⁸ is as hereinbefore defined, for example at between 0° C.    and reflux temperature in the presence of an appropriate organic    solvent (e.g. dichloromethane), or via solid phase synthesis under    conditions known to those skilled in the art;-   (d) reaction of a compound of formula VII,

wherein R¹ and R⁴¹ to R⁴⁶ are as hereinbefore defined, with a compoundof formula VIII,

wherein L² represents a leaving group such as halo, alkanesulfonate(e.g. mesylate), perfluoroalkanesulfonate or arenesulfonate (e.g. 2- or4-nitrobenzenesulfonate, toluenesulfonate or benzenesulfonate) and R²,R³, R⁴, A, B and G are as hereinbefore defined, for example at elevatedtemperature (e.g. between 35° C. and reflux temperature) in the presenceof a suitable base (e.g. triethylamine or potassium carbonate) and anappropriate organic solvent (e.g. acetonitrile, dichloromethane,chloroform, dimethylsulfoxide, N,N-dimethylformamide, a lower alkylalcohol (e.g. ethanol), isopropyl acetate or mixtures thereof);

-   (e) for compounds of formula I in which A represents CH, and R²    represents —OH or —N(H)R¹⁴, reaction of a compound of formula VII,    as hereinbefore defined, with a compound of formula IX,

wherein Y represents O or N(R¹⁴) and R³, R⁴, R¹⁴, B and G are ashereinbefore defined, for example at elevated temperature (e.g. 60° C.to reflux) in the presence of a suitable solvent (e.g. a lower allylalcohol (e.g. IPA), acetonitrile, or a mixture of a lower alkyl alcoholand water);

-   (f) for compounds of formula I in which B represents —Z—O—, reaction    of a compound of formula X,

wherein R¹, R², R³, R⁴¹ to R⁴⁶, A and Z are as hereinbefore defined,with a compound of formula XI,

wherein R⁴ and G are as hereinbefore defined, for example underMitsunobu-type conditions e.g. at between ambient (e.g. 25° C.) andreflux temperature in the presence of a tertiary phosphine (e.g.tributylphosphine or triphenylphosphine), an azodicarboxylate derivative(e.g. diethylazodicarboxylate or 1,1′-(azodicarbonyl)dipiperidine) andan appropriate organic solvent (e.g. dichloromethane or toluene);

-   (g) for compounds of formula I in which G represents N and B    represents —Z—O—, reaction of a compound of formula X, as    hereinbefore defined, with a compound of formula XII,

wherein R⁴ and L² are as hereinbefore defined, for example at between10° C. and reflux temperature in the presence of a suitable base (e.g.sodium hydride) and an appropriate solvent (e.g. N,N-dimethylformamide);

-   (h) for compounds of formula I in which R² represents —OR¹³, in    which R¹³ represents C₁₋₆ alkyl, -E-aryl or -E-Het⁶, reaction of a    compound of formula I in which R² represents OH with a compound of    formula XIII,    R^(13a)OH  XIII    wherein R^(13a) represents C₁₋₆ alkyl, -E-aryl or -E-Het⁶ and E and    Het⁶ are as hereinbefore defined, for example under Mitsunobu-type    conditions (e.g. as described hereinbefore in process step (f));-   (i) for compounds of formula I in which R² represents —OR¹³, in    which R¹³ represents C₁₋₆ alkyl, -E-aryl or -E-Het⁶, reaction of a    compound of formula XIV,

wherein R¹, R³, R⁴, R⁴¹ to R⁴⁶, A, B, G and L² are as hereinbeforedefined, with a compound of formula XIII, as hereinbefore defined, forexample at between ambient (e.g. 25° C.) and reflux temperature, underWilliamson-type conditions (i.e. in the presence of an appropriate base(e.g. KOH or NaH) and a suitable organic solvent (e.g. dimethylsulfoxideor N,N-dimethylformamide)) (the skilled person will appreciate thatcertain compounds of formula XIV (e.g. those in which L² representshalo) may also be regarded as compounds of formula I as hereinbeforedefined);(3) for compounds of formula I in which R² represents -E-NH₂, reductionof a compound of formula XV,

wherein R¹, R³, R⁴, R⁴¹ to R⁴⁶, A, B. E and G are as hereinbeforedefined, for example by hydrogenation at a suitable pressure in thepresence of a suitable catalyst (e.g. palladium on carbon) and anappropriate solvent (e.g. a water-ethanol mixture);

-   (k) for compounds of formula I in which R² represents -E-N(R¹⁴)R¹⁵,    wherein R¹⁴ represents C₁₋₆ alkyl -E-aryl -E-Het⁶, —C(O)R^(16a),    —C(O)OR^(16b), —S(O)₂R^(16c) or —C(O)N(R^(17a))R^(17b), reaction of    a compound of formula I in which R² represents -E-N(H)R¹⁵ with a    compound of formula XVI,    R^(14a)-L¹  XVI    wherein R^(14a) represents C₁₋₆ alkyl, -E-aryl -E-Het⁶,    —C(O)R^(16a), —C(O)OR^(16b), —S(O)₂R^(16c) or    —C(O)N(R^(17a))R^(17h), and R^(16a), R^(16b), R^(16c), R^(17a),    R^(17b), Het⁶, E and L¹ are as hereinbefore defined, for example    under conditions described hereinbefore (process step (a));-   (l) for compounds of formula I in which R² represents    -E-N(R¹⁵)C(O)N(H)R^(17a), reaction of a compound of formula I in    which R² represents -E-N(H)R¹⁵ with a compound of formula XVII,    R^(17a)—N═C═O  XVII    wherein R^(17a) is as hereinbefore defined, for example under    conditions described hereinbefore (process step (c));-   (m) for compounds of formula I in which R² represents    -E-N(H)[C(O)]₂NH₂, reaction of a compound of formula I in which R²    represents -E-NH₂ with oxalic acid diamide, for example at between    −10 and 25° C. in the presence of a suitable coupling agent (e.g.    1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), an appropriate    activating agent (e.g. 1-hydroxybenzotriazole), a suitable base    (e.g. triethylamine) and a reaction-inert solvent (e.g.    N,N-dimethylformamide);-   (n) for compounds of formula I in which R² represents    -E-N(H)C(NH)NH₂, reaction of a compound of formula I in which R²    represents -E-NH₂ with a compound of formula XVIII,    R²³O—C(═NH)NH₂  XVIII    or an N-protected derivative thereof, wherein R²³ is as hereinbefore    defined, for example at between room and reflux temperature,    optionally in the presence of a suitable solvent (e.g. toluene)    and/or an appropriate acidic catalyst (e.g. acetic acid at, for    example, 10 mol %);-   (o) for compounds of formula I in which R² represents —OR³, in which    R¹³ represents —C(O)R^(16a), —C(O)OR^(16b) or    —C(O)N(R^(17a))R^(17b), reaction of a compound of formula I in which    R² represents —OH with a compound of formula XIX,    R^(13b)-L³  XIX    is wherein R^(13b) represents —C(O)R^(16a), —C(O)OR^(16b) or    C(O)N(R^(17a))R^(17b), L³ represents a leaving group such as halo,    p-nitrophenoxy, —OC(O)R^(16a), —OC(O)OR^(16b), —OH or imidazole and    R^(16a), R^(16b), R^(17a) and R^(17b) are as hereinbefore defined,    for example at between −10° C. and reflux temperature in the    presence of a suitable base (e.g. triethylamine, pyridine or    potassium carbonate), an appropriate organic solvent (e.g. THF,    dichloromethane or acetonitrile) and (where appropriate) a suitable    coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide);    (p) for compounds of formula I in which R² represents H or —OH and    R³ represents H, reduction of a compound of formula I in which R²    and R³ together represent ═O, in the presence of a suitable reducing    agent and under appropriate reaction conditions; for example, for    formation of compounds of formula I in which R² represents OH,    reduction may be performed under mild reaction conditions in the    presence of e.g. sodium borohydride and an appropriate organic    solvent (e.g. THF); for formation of compounds of formula I in which    R² represents OH, wherein the compound is enantiomerically enriched    (or is a single enantiomer) at the chiral centre to which R² is    attached, reduction may be performed enzymatically (for example    under conditions known to those skilled in the art, such as in the    presence of horse liver alcohol dehydrogenase and NADPH) or by    hydrogenation in the presence of a suitable solution-phase    (homogeneous) catalyst under conditions known to those skilled in    the art; and for formation of compounds of formula I in which R²    represents H, reduction may be performed either under Wolff-Kischner    conditions known to those skilled in the art or by activating the    relevant C═O group using an appropriate agent (such as    tosylhydrazine) in the presence of a suitable reducing agent (e.g.    sodium borohydride or sodium cyanoborohydride) and an appropriate    organic solvent (e.g. a lower (e.g. C₁₋₆) alkyl alcohol);-   (q) for compounds of formula I in which R² represents halo,    substitution of a corresponding compound of formula I in which R²    represents —OH, using an appropriate halogenating agent (e.g. for    compounds in which R² represents fluoro, reaction with    (diethylamino)sulfur trifluoride);-   (r) for compounds of formula I in which R² and R³ represent H, A    represents -J- and B represents —N(R²⁰)—Z— (wherein —N(R²⁰) is    attached to the carbon atom bearing R² and R³), reaction of a    compound of formula XX,

wherein R¹, R², R³, R²⁰, R⁴¹ to R⁴⁶ and J are as hereinbefore defined,with a compound of formula XXI,

wherein R⁴, G, Z and L² are as hereinbefore defined, for example atelevated temperature (e.g. 40° C. to reflux) in the presence of asuitable organic solvent (e.g. acetonitrile);

-   (s) for compounds of formula I in which A represents C₂ alkylene and    R² and R³ together represent ═O, reaction of a compound of formula    VII, as hereinbefore defined, with a compound of formula XXII,

wherein B, G and R⁴ are as hereinbefore defined, for example at betweenroom and reflux temperature in the presence of a suitable base (e.g.triethylamine, potassium carbonate or tetrabutylammonium hydroxide) andan appropriate organic solvent (e.g. a lower alkyl (e.g. C₁₋₆) alcohol);

-   (t) for compounds of formula I in which R¹ represents —C(O)XR⁷,    —C(O)N(R⁸)R^(5d) or —S(O)₂R⁹, reaction of a compound of formula    XXIII,

wherein R^(1a) represents —C(O)XR⁷, —C(O)N(R⁸)R^(5d) or —S(O)₂R⁹ andR^(5d), R⁷, R⁸, R⁹, R⁴¹ to R⁴⁶ and L² are as hereinbefore defined, witha compound of formula XXIV,

wherein R², R³, R⁴, A, B and G are as hereinbefore defined, for exampleat between room and reflux temperature in the presence of a suitablebase (e.g. sodium hydrogencarbonate or potassium carbonate) and anappropriate organic solvent (e.g. acetonitrile);

-   (u) for compounds of formula I which are oxabispidine-nitrogen    NV-oxide derivatives, oxidation of the corresponding oxabispidine    nitrogen of a corresponding compound of formula I, in the presence    of a suitable oxidising agent (e.g. mCPBA), for example at 0° C. in    the presence of a suitable organic solvent (e.g. dichloromethane);-   (v) for compounds of formula I which are C₁₋₄, alkyl quaternary    ammonium salt derivatives, in which the alkyl group is attached to a    oxabispidine nitrogen, reaction, at the oxabispidine nitrogen, of a    corresponding compound of formula I with a compound of formula XXV,    R²⁵-L⁴  XXV    wherein R²⁵ represents C₁₋₄ alkyl and L⁴ is a leaving group such as    halo, alkanesulfonate or arenesulfonate, for example at room    temperature in the presence of an appropriate organic solvent (e.g.    N,N-dimethylformamide), followed by purification (using e.g. HPLC)    in the presence of a suitable counter-ion provider (e.g. NH₄OAc);-   (w) conversion of one R⁴ substituent to another using techniques    well known to those skilled in the art; or-   (x) introduction of one or more (further) R⁴ substituents to the    aromatic ring using techniques well known to those skilled in the    art (e.g. chlorination).

Compounds of formula II may be prepared by reaction of a compound offormula XXVI,

wherein R⁴¹ to R⁴⁶ are as hereinbefore defined, with a compound offormula VIII as, hereinbefore defined, for example as describedhereinbefore for the synthesis of compounds of formula I (process step(d)), or, in the case of compounds of formula II wherein A representsCH₂ and R² represents —OH or N(H)R¹⁴, wherein R¹⁴ is as hereinbeforedefined, with a compound of formula IX as hereinbefore defined, forexample as described hereinbefore for the synthesis of compounds offormula I (process step (e)).

Compounds of formula IV may be prepared by reaction of a compound offormula II, as hereinbefore defined, with a compound of formula XXVII,L¹-C(O)-L¹  XXVIIwherein L¹ is as hereinbefore defined, and in which the two L¹ groupsmay be the same or different, for example at between 0° C. and refluxtemperature in the presence of a suitable base (e.g. triethylamine orpotassium carbonate) and an appropriate organic solvent (e.g. toluene ordichloromethane).

Compounds of formula VII may be prepared by reaction of a compound offormula XXVI, as hereinbefore defined, with a compound of formula III,as hereinbefore defined, for example as described hereinbefore for thesynthesis of compounds of formula I (process step (a)), or, in the caseof compounds of formula VII wherein R¹ represents —C(O)N(H)R⁸, with acompound of formula VI, as hereinbefore defined, for example asdescribed hereinbefore for the synthesis of compounds of formula I(process step (c)).

Compounds of formula VII wherein R¹ represents —C(O)XR⁷ or—C(O)N(R⁸)R^(5d) may alternatively be prepared by reaction of a compoundof formula XXVI, as hereinbefore defined, with a compound of formulaXXVII, as hereinbefore defined, for example as described hereinbeforefor the synthesis of compounds of formula IV, followed by reaction ofthe resultant intermediate with a compound of formula V, as hereinbeforedefined, for example as described hereinbefore for the synthesis ofcompounds of formula I (process step (b)).

Compounds of formula VIII may be prepared by standard techniques. Forexample, compounds of formula VIII in which:

-   (1) B represents —Z—O— may be prepared by coupling a compound of    formula XI, as hereinbefore defined, to a compound of formula    XXVIII,    L²-Z—C(R²)(R³)-A-L²  XXVIII-    wherein R², R³, A, Z and L² are as hereinbefore defined, and the    two L² groups may be the same or different; or-   (2) B represents —C(O)N(R²⁰)— may be prepared by coupling a compound    of formula XXIX,

-    wherein G, R⁴ and R²⁰ are as hereinbefore defined, to a compound of    formula XXX,    L⁵-C(O)—C(R²)(R³)-A-L²  XXX-    wherein L⁵ represents a suitable leaving group (e.g. —OH or halo)    and R², R³, A and L² are as hereinbefore defined;    in both cases, under conditions which are well known to those    skilled in the art.

Compounds of formula VIII in which A represents —(CH₂)₂—, R² and R³ bothrepresent H, B represents —CH₂— and G represents CH may be prepared byreaction of a compound of formula XXXA,

wherein R⁴ as is hereinbefore defined, but preferably comprises a singleortho- or para-directing substitutable group, such as halo, withsuccinic anhydride under standard Friedel-Crafts acylation conditions,followed by:

-   (i) reduction of the resultant intermediate (which may be a two-step    process);-   (ii) conversion of the terminal hydroxy group to an appropriate L²    group; and, if necessary,-   (iii) conversion of one R⁴ group to another,    all of which steps may be carried out under conditions that are well    known to those skilled in the art.

Compounds of formula VIII in which A represents C₁₋₆ alkylene, Brepresents a direct bond or C₁₋₄ alkylene, R² and R³ independentlyrepresent H or C₁₋₆ alkyl, provided that when A represents C₁ alkyleneand B represents a single bond, R² and R³ both represent H, and Grepresents CH, may be prepared by coupling a compound of formula XXXB,

wherein Hal represents fluoro, chloro, bromo or iodo and R⁴ is ashereinbefore defined, to a compound of formula XXXC,

wherein R^(2a) and R^(3a) represent H or C₁₋₆ alkyl as appropriate,A^(a) represents a direct bond or C₁₋₄ alkylene, B^(b) represents adirect bond or C₁₋₄ alkylene, and Hal, R² and R³ are as hereinbeforedefined, or with a vinyl magnesium halide, for example at between −25°C. and room temperature in the presence of a suitable zinc(II) salt(e.g. anhydrous ZnBr₂), an appropriate catalyst (e.g. Pd(PPh₃)₄ orNi(PPh₃)₄) and a reaction-inert organic solvent (e.g. THF, toluene ordiethyl ether), followed by:

-   (i) reduction of the resultant intermediate, in the presence of a    suitable borane or borane-Lewis base complex (e.g. borane-dimethyl    sulfide), an appropriate solvent (e.g. diethyl ether, THF, or a    mixture thereof);-   (ii) oxidation of the resulting borane adduct with a suitable    oxidising agent (e.g. sodium perborate); and-   (iii) conversion of the resulting OH group to an L² group under    conditions known to those skilled in the art.

Compounds of formula VIII in which A represents a direct bond or C₁₋₆alkylene, B represents C₂₋₄ alkylene, R² and R³ independently representH or C₁₋₆ alkyl and G represents CH may be prepared by coupling acompound of formula XXXD,

wherein A^(b) represents a direct bond or C₁₋₆ alkylene, B^(c)represents a direct bond or C₁₋₂ alkylene, and R^(2a) and R^(3a) are ashereinbefore defined, or a terminal alkyne equivalent thereof, with acompound of formula XXXB as hereinbefore defined, for example understandard metal-catalysed vinylation conditions, such as Heck conditions(for example in the presence of suitable palladium catalyst system (e.g.Pd(OAc)₂ and o-tolylphosphine), for example at between room and refluxtemperature in the presence of a suitable solvent (e.g. THF, DMF,dimethyl ether, toluene, water, ethanol or mixtures thereof) andoptionally in the presence of an appropriate base (e.g. triethylamine)),or, where the reaction is carried out using a terminal alkyne, undercoupling conditions that will be known to those skilled in the art (forexample at between room and reflux temperature in the presence of asuitable solvent (e.g. THF, DMF, dimethyl ether, toluene, water, ethanolor mixtures thereof), an appropriate base (e.g. diethylamine) andoptionally in the presence of a suitable catalyst (e.g. a copper saltsuch as copper(I) iodide)), followed by:

-   (i) hydrogenation of the resultant alkene (or alkyne) intermediate,    for example in the presence of a suitable supported palladium    catalyst (e.g. Pd on CaCO₃ or Pd/C), for example at room temperature    in the presence of a suitable solvent (e.g. a lower alkyl alcohol,    such as methanol); and-   (ii) conversion of the OH group to an L² group, under conditions    known to those skilled in the art.

Compounds of formula VIII in which the group -A-C(R²)(R³)—B— represents—(CH₂)₃₋₁₁— may be prepared by reaction of a corresponding compound offormula VIII in which the group -A-C(R²)(R³)—B— represents —(CH₂)₁₋₉—with diethylmalonate using standard malonic ester synthesis, followedby:

-   (i) reduction of the resultant intermediate; and-   (ii) conversion of the terminal hydroxy group to an appropriate L²    group, both of which steps may be carried out under conditions that    are well known to those skilled in the art.

Compounds of formula VIII in which A represents C₁₋₆ alkylene, Brepresents —Z—N(R²⁰)— (in which latter case, Z is attached to the carbonatom bearing R² and R³), G represents CH and Z and R²⁰ are ashereinbefore defined, may be prepared by coupling a compound of formulaXXXB as hereinbefore defined, to a compound of formula XXXE,

wherein A^(c) represents C₁₋₆ alkylene and Z, R²⁰, R² and R³ are ashereinbefore defined, for example at elevated temperature underconditions well known to those skilled in the art, followed byconversion of the hydroxy group to an L² group under conditions known tothose skilled in the art (for example, where the L² group isp-toluenesulfonato, the conversion may be carried out by reactionbetween the intermediate hydroxy compound and p-toluenesulfonyl chloridein the presence of a suitable base (e.g. triethylamine) and anappropriate solvent (e.g. dichloromethane), and optionally in thepresence of a suitable catalyst (e.g. DMAP, for example at between 0.1and 10% (w/w) (e.g. 1% (w/w)) relative to mass of the intermediatehydroxy compound).

Compounds of formula VIII in which A represents a direct bond or C₁₋₆alkylene, B represents C₁₋₄ alkylene and G represents N may be preparedby coupling a compound of formula XXXF

wherein R⁴ is as hereinbefore defined, to a compound of formula XXXG,

wherein B^(c) represents a direct bond or C₁₋₃ alkylene and A^(c), L²,L⁵, R² and R³ are as hereinbefore defined, for example by reacting thecompound of formula XXXF with a strong base such as butyl lithium orphenyl lithium (e.g. at −60° C., in the presence of a polar solvent,such as THF), followed by addition of the deprotonated intermediate to acompound of formula XXXG (e.g. at −65° C.) in the presence of a suitablesolvent (such as THF).

Compounds of formula VIII in which A represents C₂ alkylene and R²represents —OR¹³, in which R¹³ represents C₁₋₆ alkyl, -E-aryl or -E-Het⁶may alternatively be prepared by reaction of a compound of formula XIII,as hereinbefore defined, with a compound of formula XXXI,

wherein R³, R⁴, R²⁵, B and G are as hereinbefore defined, for example atbetween ambient temperature (e.g. 25° C.) and reflux temperature in thepresence of a suitable base (e.g. potassium carbonate) and anappropriate organic solvent (e.g. acetonitrile), followed by conversionof the ester functionality to an L² group (in which L² is ashereinbefore defined), under conditions that are well known to thoseskilled in the art.

Compounds of formula IX may be prepared in accordance with techniqueswhich are known to those skilled in the art. For example, compounds offormula IX in which:

-   (1) B represents —CH₂O— and Y represents 0 may be prepared by    reaction of a compound of formula XI, as hereinbefore defined, with    a compound of formula XXXII

-    wherein R³ and L² are as hereinbefore defined, for example at    elevated temperature (e.g. between 60° C. and reflux temperature) in    the presence of a suitable base (e.g. potassium carbonate or NaOH)    and an appropriate organic solvent (e.g. acetonitrile or    toluene/water), or as otherwise described in the prior art;-   (2) R³ represents H, B represents a direct bond, C₁₋₄ alkylene,    —Z—N(R²⁰)—, —Z—S(O)_(n)— or —Z—O— (in which, in each case, the group    —Z represents C₁₋₄ alkylene attached to the carbon atom bearing R³)    and Y represents O may be prepared by reduction of a compound of    formula XXXIIIA or XXXIIIB,

-    wherein B^(a) represents —Z^(a)—N(R²⁰), —Z^(a)—S(O)_(n)— or    —Z^(a)—O— (in which groups Z^(a) represents a direct bond or C₁₋₃    alkylene attached to the carbon atom bearing R³), and B^(b), R⁴,    R²⁰, G and n are as hereinbefore defined, for example at between    −15° C. and room temperature in the presence of a suitable reducing    agent (e.g. NaBH₄) and an appropriate organic solvent (e.g. THF),    followed by an internal displacement reaction in the resultant    intermediate, for example at room temperature in the presence of a    suitable base (e.g. potassium carbonate) and an appropriate organic    solvent (e.g. acetonitrile);-   (3) B represents a direct bond, C₁₋₄ alkylene, —Z—N(R²⁰)—, —Z—S(O)₂—    or —Z—O— (in which, in each case, the group Z represents C₁₋₄    alkylene attached to the carbon atom bearing R³) and Y represents O    may be prepared by oxidation of a compound of formula XXXIVA or    XXXIVB,

-    wherein R³, R⁴, B^(a), B^(b) and G are as hereinbefore defined, in    the presence of a suitable oxidising agent (e.g. mCPBA), for example    by refluxing in the presence of a suitable organic solvent (e.g.    dichloromethane); or-   (4) B represents —Z—O—, in which group Z represents C₁₋₄ alkylene    attached to the carbon atom bearing R³, and Y represents —N(R¹⁴),    wherein R¹⁴ represents —C(O)OR^(16b) or —S(O)₂R^(16c), may be    prepared by cyclisation of a compound of formula XXXV,

-    wherein R^(14b) represents —C(O)OR^(16b) or —S(O)₂R^(16c), Z^(b)    represents C₁₋₄ alkylene attached to the carbon atom bearing R³ and    R³, R⁴, R^(16b), R^(16c), G and L² are as hereinbefore defined, for    example at between 0° C. and reflux temperature in the presence of a    suitable base (e.g. sodium hydroxide); an appropriate solvent (e.g.    dichloromethane, water, or a mixture thereof) and, if necessary, a    phase transfer catalyst (such as tetrabutylammonium    hydrogensulfate).

Compounds of formula X may be prepared in a similar fashion to compoundsof formula I (see, for example process steps (a) to (e)).

Compounds of formula XIV may be prepared by replacement of the —OH groupof a compound of formula I in which R² represents —OH with an L² groupunder conditions that are known to those skilled in the art.

Compounds of formula XV in which E represents a direct bond may beprepared by reaction of a compound of formula I in which R² represents—OH with a compound of formula XXXVI,R²⁶S(O)₂Cl  XXXVIwherein R²⁶ represents C₁₋₄ alkyl or aryl (which two groups areoptionally substituted by one or more substituents selected from C₁₋₄alkyl, halo and nitro), for example at between −10 and 25° C. in thepresence of a suitable is solvent (e.g. dichloromethane), followed byreaction with a suitable source of the azide ion (e.g. sodium azide),for example at between ambient and reflux temperature in the presence ofan appropriate solvent (e.g. N,N-dimethylformamide) and a suitable base(e.g. sodium hydrogencarbonate).

Compounds of formula XV may alternatively be prepared by reaction of acompound of formula VII, as hereinbefore defined, with a compound offormula XXXVII,

wherein R³, R⁴, A, B, E, G and L² are as hereinbefore defined, forexample under analogous conditions to those described hereinbefore forthe synthesis of compounds of formula I (process step (d)).

Compounds of formula XX may be prepared by removing an optionallysubstituted benzyloxycarbonyl unit from (i.e. deprotecting) acorresponding compound of formula I in which B represents—N(R²⁰)C(O)OCH₂— and A represents J, wherein R²⁰ and J are ashereinbefore defined, for example under conditions which are known tothose skilled in the art.

Compounds of formula XXIII may be prepared by reaction of a compound offormula XXXVIII,

wherein the wavy bonds indicate optional E-, Z- or mixed E- andZ-geometry about the double bonds, and R^(1a) and R⁴¹ to R⁴⁶ are ashereinbefore defined, with water and a suitable source of themercury(II) ion (e.g. mercury(II) acetate), for example at between 0 and30° C., optionally in the presence of an appropriate organic solvent(e.g. THF), followed by the conversion of the two resulting mercurialkylfunctions to L² groups, wherein L² is as hereinbefore defined, underconditions known to those skilled in the art (for example, in the casewhere L² represents iodo, reaction with iodine at between room andreflux temperature in the presence of a suitable solvent (e.g.chloroform, water or a mixture thereof)).

Compounds of formula XXIII may alternatively be prepared by reaction ofa compound of formula XXXIX,

wherein R^(1a) and R⁴¹ to R⁴⁶ are as hereinbefore defined, with areagent that will convert the two —OH functionalities to L² groups underconditions known to those skilled in the art. For example, thisconversion may be achieved, in the case of compounds of formula XXIIIwherein L² represents chloro, bromo or iodo, by reaction of a compoundof formula XXXIX with a suitable halogenating agent (for example:triphenylphosphine or bis(diphenylphosphino)ethane combined with thehalogen (e.g. bromine or iodine)) in the presence of a suitable base(e.g. imidazole) and a suitable solvent (e.g. dichloromethane, etherand/or acetonitrile), for example as described in Synth. Commun. 1990,20(10), 1473. Suitable halogenating agents also include:triphenylphosphine combined with carbon tetrachloride, carbontetrabromide, hexachloroethane or hexachloroacetone; triphenylphosphinedibromide; or triphenylphosphine combined with diethylazodicarboxylateand methyl iodide. In the case of compounds of formula XXIII wherein L²represents an arenesulfonate or alkanesulfonate (e.g.p-toluenesulfonate, 2- or 4-nitrobenzenesulfonate, methanesulfonate ortrifluoromethanesulfonate), the conversion may alternatively be achievedby reaction of a compound of formula XXXIX with an appropriatearenesulfonyl or alkanesulfonyl derivative (e.g. p-toluenesulfonylchloride, 4-nitrobenzenesulfonyl chloride or trifluoromethanesulfonicanhydride), in the presence of a suitable base (e.g. triethylamine,pyridine or N,N-diisopropylethylamine) and an appropriate organicsolvent (e.g. dichloromethane or acetonitrile).

Compounds of formula XXVI (or an N-protected derivative thereof) may beprepared from a corresponding compound of formula XL,

or an N-protected derivative thereof (e.g. where the protecting group isan R^(1a) group, wherein R^(1a) is as hereinbefore defined), wherein R⁴¹to R⁴⁶ and L² are as hereinbefore defined, with ammonia (or a protectedderivative thereof (e.g. benzylamine)), for example under conditionsdescribed hereinbefore for the synthesis of compounds of formula I(process step (t)).

Compounds of formula XXXVII may be prepared in analogous fashion tocompounds of formula XV (i.e. from the corresponding alcohol).

Compounds of formula XXXVIII may be prepared by reaction of a compoundof formula XLI,

wherein the wavy bonds indicate optional E-, Z- or mixed E- andZ-geometry about the double bonds, and R⁴¹ to R⁴⁶ are as hereinbeforedefined, with a compound of formula III in which R¹ represents —C(O)XR⁷,—C(O)N(R⁸)R^(5d) or —S(O)₂R⁹, wherein R^(5d), R⁷, R⁸ and R⁹ are ashereinbefore defined, for example at between −10 and 25° C. in thepresence of a suitable base (e.g. NaOH, triethylamine, pyridine orpotassium carbonate) and an appropriate solvent (e.g. ether, water,dichloromethane, THF, or mixtures thereof).

Compounds of formula XXXIX may be prepared by reaction of a compound offormula XLII,

wherein the wavy bonds indicate optional R-, S- or mixed R- andS-stereochemistry at the asymmetric carbon atoms, and R^(1a) and R⁴¹ toR⁴⁶ are as hereinbefore defined, with water, for example at between roomand reflux temperature in the presence of a suitable catalyst (e.g. aprotic acid such as sulfuric, methanesulfonic or trifluoroacetic acid,an acidic ion-exchange resin such as Amberlyst® 15 or Nafion®, a Lewisacid such as ZnSO₄ or Yb(III) trifluoromethanesulfonate or a base suchas sodium hydroxide or tetrabutylammonium hydroxide), an appropriatesolvent (e.g. THF, water, 1,4-dioxane or 1-methyl-2-pyrrolidinone, ormixtures thereof (e.g. THF/water)), and optionally (when a basiccatalyst is used) in the presence of a suitable phase transfer catalyst(e.g. Triton® B).

The reaction may be advantageously be performed using compounds offormula XLII having enantiomeric (or diastereomeric) enrichment at thechiral centres identified above. The use of such enantiomerically- (ordiastereomerically-) enriched compounds of formula XLII in the formationof compounds of formula XXXIX may have the advantage that a greaterproportion of the product diol is obtained as the cis-isomer (i.e. theconformation of compounds of formula XXXIX depicted above). Thoseskilled in the art will appreciate that such an increased proportion ofcis-isomer may be retained in the conversion of compounds of formulaXXXIX to compounds of formula XXIII, and thus may eventually lead to ahigher yield of compounds of formula I (via process step (t)).

The reaction may also be advantageously performed using compounds offormula XLII wherein R^(1a) represents —S(O)₂R⁹ (e.g. wherein R⁹represents optionally substituted phenyl, such as 2- or 4-fluorophenyl,2- or 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2-or 4-nitrophenyl, 2,4,6-trimethylphenyl). The use of suchring-substituted benzenesulfonyl derivatives may have the advantage thatpurification of the resulting compound of formula XXXIX may be made morestraightforward (e.g. requiring only a simple recrystallisation step)and/or that, in a compound of formula I (synthesised via compounds offormulae XXXIX and XXIII), removal of the —S(O)₂R⁹ group (allowing itsreplacement with another R¹ group) may be made more straightforward(e.g. enabling the use of milder reaction conditions).

Compounds of formula XL may be prepared in an analogous fashion tocompounds of formula XXIII, as hereinbefore defined (i.e. from e.g. thecorresponding diallylamine).

Compounds of formula XLII in which the substituent R⁴² has the sameidentity as R⁴¹, R⁴⁴ has the same identity as R⁴³ and R⁴⁶ has the sameidentity as R⁴⁵ may be prepared by reaction of two or more equivalentsof a compound of formula XLIII,

wherein the wavy bond indicates optional R-, S- or mixed R- andS-stereochemistry at the asymmetric carbon atom, and R⁴¹, R⁴³, R⁴⁵ andL² are as hereinbefore defined, with one equivalent of a compound offormula XLIV,R^(1a)NH₂  XLIVwherein R^(1a) is as hereinbefore defined, for example at between roomand reflux temperature in the presence of a suitable base (e.g. analkali metal carbonate such as cesium carbonate, sodium hydroxide,sodium hydride or lithium diisopropylamide), an appropriate solvent(e.g. acetonitrile, N,N-dimethylformamide, THF, toluene, water ormixtures thereof), and optionally in the presence of a phase transfercatalyst (e.g. tricaprylyl-methylammonium chloride). Preferred basesinclude sodium hydroxide and preferred solvents include water. Thereaction is advantageously performed with compounds of formula XLIVwherein R^(1a) represents —S(O)₂R⁹ (e.g. wherein R⁹ representsoptionally substituted phenyl, such as 2- or 4-fluorophenyl, 2- or4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- or4-nitrophenyl, 2,4,6-trimethylphenyl). The use of such ring-substitutedbenzenesulfonyl derivatives may have the advantage that purification ofthe resulting compound of formula XLII may be made more straightforward(e.g. requiring only a simple recrystallisation step).

Compounds of formulae XLIII and XLIV may also be reacted together inthis way in the presence of water in order to give a direct, “one-pot”process providing a compound of formula XXXIX. Such “one-pot” reactionsmay be carried out, for example, by using a biphasic reaction mixturecomprising a solution of XLIII and XLIV in an organic solvent (e.g.toluene), and an aqueous solution of a base (e.g. sodium hydroxide).Alternatively, the aqueous solution of base may, after the formation ofthe intermediate compound of formula XLII is complete, be exchanged foran aqueous solution of an acid (e.g. either a protic or a Lewis acid).Any of the reaction steps in such biphasic mixtures may be carried outin the presence of a suitable phase transfer catalyst.

Compounds of formula XLII having enantiomeric (or diastereomeric)enrichment at the chiral centres identified above may be prepared byreaction of a compound of formula XLIV, as hereinbefore defined, with acompound of formula XLIII, as hereinbefore defined, having enantiomericenrichment at the carbon atom to which R⁴³ is attached. Those skilled inthe art will realise that this will lead to more of the isomer(s)required for further elaboration to compounds of formula I.

Compounds of formula XLII may alternatively be prepared by reaction of acompound of formula XXXVIII, as hereinbefore defined, with a suitableoxidising agent. Suitable conditions for this oxidation include, forexample, reaction at between −25° C. and reflux temperature with asuitable peroxide or peracid (e.g. hydrogen peroxide, tert-butylhydroperoxide or mCPBA), optionally in the presence of an appropriatesolvent (e.g. dichloromethane, t-butanol, nitromethane, toluene, water,or mixtures thereof), a suitable catalyst (for example a protic acid, aLewis acid, or a metal complex capable of forming a peroxide adduct,such as methyltrioxorhenium(VII) or a combination of sodium tungstateand (aminomethyl)phosphonic acid), and/or further appropriate additives(for example: in the case of oxidations carried out withmethyltrioxorhenium(VII) and hydrogen peroxide, a basic additive such aspyridine or pyrazole; and in the case of oxidations with sodiumtungstate and hydrogen peroxide, a phase transfer catalyst such asmethyltri-n-octylammonium hydrogensulfate). Particular embodiments ofthis oxidation are described in patent applications EP A1 0 380 085 andWO 98/33786 A1, the disclosures in which documents are herebyincorporated by reference. When the oxidation is carried out in thepresence of both a catalyst and water, one embodiment of the reactioninvolves a “one-pot” conversion of the compound of formula XXXVIII to acompound of formula XXXIX, as hereinbefore defined. This reactionproceeds via the catalysed hydrolysis of the intermediate compound offormula XLII.

Compounds of formula XLII in which the two epoxide chains are notidentical (e.g. where R⁴¹ and R⁴² are not identical) may be prepared byreaction of a compound of formula XLIII, as hereinbefore defined, with acompound of formula XLV,

wherein the wavy bond indicates optional R-, S- or mixed R- andS-stereochemistry at the asymmetric carbon atom, and R^(1a), R⁴², R⁴⁴,and R⁴⁶ are as hereinbefore defined, for example under conditionsdescribed hereinbefore for the synthesis of symmetrical compounds offormula XLII.

Compounds of formula XLV may be prepared by reaction of one or moreequivalents of a compound of formula XLIV, as hereinbefore defined, withone equivalent of a compound of formula XLIII, for example underconditions as described hereinbefore for reaction between these twocompounds.

Compounds of formula XLV may alternatively be prepared by oxidation of acorresponding compound of formula XLVI,

wherein the wavy bond indicates optional E-, Z- or mixed E- andZ-geometry about the double bond, and R^(1a), R⁴², R⁴⁴ and R⁴⁶ are ashereinbefore defined, for example under conditions as hereinbeforedescribed for the synthesis of compounds of formula XLII.

Compounds of formula I may also be prepared, advantageously, bydehydrative cyclisation of compound of formula XLVII,

wherein A, B, G, R¹, R², R³, R⁴ and R⁴¹ to R⁴⁶ are as hereinbeforedefined, for example in the presence of a suitable dehydrating agent(such as: a strong acid (e.g. sulfuric acid (e.g. concentrated sulfuricacid), methanesulfonic acid (e.g. anhydrous methanesulfonic acid) andthe like; an acid anhydride such as acetic anhydride ortrifluoromethane-sulfonic anhydride; P₂O₅ in methanesulfonic acid; aphosphorous-based halogenating agent such as P(O)Cl₃, PCl₃ or PCl₅; andthionyl chloride).

This cyclisation process may be carried out in the presence of asuitable organic solvent system, which solvent system should notsignificantly react chemically with, or significantly give rise tostereochemical changes in, the reactants or product once formed, orsignificantly give rise to other side reactions. Preferred solventsystems include aromatic hydrocarbons (e.g. toluene or xylene).

This cyclisation process may be carried out at elevated temperature(e.g. up to the reflux temperature of the relevant solvent system, orhigher if a pressurised system is employed). Clearly, appropriatereaction times and reaction temperatures depend upon the solvent systemthat is employed, as well as the reactants that are used and thecompound that is to be formed, but these may be determined routinely bythe skilled person.

Compounds of formula XLVII may advantageously be prepared by reaction ofa compound of formula XLVIII,

wherein the wavy bonds indicate optional R-, S- or mixed R- andS-stereochemistry at the asymmetric carbon atoms, and R¹ and R⁴¹ to R⁴⁶are as hereinbefore defined, with a compound of formula XXIV ashereinbefore defined. This reaction may be carried out at between roomtemperature and the reflux temperature of any solvent that is employed.Suitable solvent systems that may be employed include organic solventsystems, which system should not significantly react chemically with, orsignificantly give rise to stereochemical changes in, the reactants orproduct once formed, or significantly give rise to other side reactions.Preferred solvent systems include lower alkyl alcohols (particularlyprimary alcohols (e.g. ethanol)) optionally in the presence of water,IMS, aromatic hydrocarbons (e.g. toluene) or mixtures thereof.

Compounds of formula XXIV may be prepared as described herein. Compoundsof formula XLVIII may be prepared according to or by analogy with theprocedures described herein in relation to the preparation of compoundsof formula XLII.

The formation of compounds of formula XLVII may be also be performedusing compounds of formula XLVIII having enantiomeric (ordiastereomeric) enrichment at the chiral centres identifiedhereinbefore. The use of such enantiomerically- (or diastereomerically-)enriched compounds of formula XLVIII in the formation of compounds offormula XLVII may have the advantage that a greater proportion of theproduct diol is obtained in a form (e.g. the trans-form) whichfacilitates the subsequent cyclisation, leading to a higher yield ofcompounds of formula I.

The formation of compounds of formula XLVII is preferably carried outusing compounds of formula XLVIII in which R¹ represents R^(1a), whereinR^(1a) is as hereinbefore defined. The formation of compounds of formulaXLVII is more preferably carried out using compounds of formula XLVIIIin which R¹ represents —S(O)₂R⁹ (e.g. wherein R⁹ represents optionallysubstituted phenyl, such as 2- or 4-fluorophenyl, 2- or 4-chlorophenyl,4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- or 4-nitrophenyl,2,4,6-trimethylphenyl and, especially, unsubstituted phenyl).

Preferred compounds of formula XXIV include those in which:

-   G represents CH;-   A represents a direct bond;-   B represents a direct bond;-   R² represents H or C₁₋₆ alkyl-   R³ represents H or C₁₋₆ alkyl;-   R⁴ is absent or represents one to three halo, methyl, methoxy or    nitro groups, especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo,    4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro.

We have found, surprisingly, that, when compounds of formula I areformed using this process (i.e. via compounds of formula XLVII), theemployment of derivatives of formula XLVIII in which R¹ representsR^(1a) (e.g. wherein R^(1a) represents optionally-substitutedbenzenesulfonyl, such as described above), and benzylamine-typederivatives of formula XXIV (such as those described above), may havethe advantage that, in the resultant compound of formula I, the presenceof the R^(1a) (e.g. —S(O)₂R⁹ group and/or the benzylamine-type groupallows for direct and facile replacement of that/those group(s) withother R¹ groups, and/or

fragments, as appropriate, for example by employing reactions that areakin to “deprotection” reactions (see below), and subsequentlyperforming coupling reactions (see, for example process steps (a), (c),(d) and (e)). We have found, if that benzenesulfonyl derivatives offormula XLVIII, and benzylamine-type derivatives of formula XXIV areemployed, subsequent replacement steps may be made more straightforward(e.g. enabling the use of milder reaction conditions).

In this respect, certain compounds of the invention may further beemployed as intermediates, useful in the manufacture of other compoundsof the invention. Such compounds include, but are not limited tocompounds of formula I in which:

-   R¹ represents —S(O)₂R⁹, wherein R⁹ represents optionally substituted    phenyl, such as 2- or 4-fluorophenyl, 2- or 4-chlorophenyl,    4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- or 4-nitrophenyl,    2,4,6-trimethylphenyl and, especially, unsubstituted phenyl;-   R⁴¹ to R⁴⁶ all represent H;-   G represents CH;-   A represents a direct bond;-   B represents a direct bond;-   R² represents H or C₁₋₆ alkyl;-   R³ represents H or C₁₋₆ alkyl;-   R⁴ is absent or represents one to three halo, methyl, methoxy or    nitro groups, especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo,    4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro.

Compounds of formula I that may, in particular, be employed asintermediates include, but are not limited to those in which:

-   R² and R³ both represent H;-   R⁴ is absent; and/or-   R⁹ represents unsubstituted phenyl.

Further, compounds of formula I in which:

-   R⁴¹ to R⁴⁶ all represent H;-   R¹ represents straight- or branched-chain C₁₋₄ alkyl (e.g. C₁₋₃    alkyl, such as methyl) terminated by C(O)R^(5a) or    —N(H)C(O)OR^(10b);-   R^(5a) and R^(10b) independently represent straight- or    branched-chain C₂₋₆ alkyl (e.g. C₃₋₅ alkyl, such butyl (e.g.    t-butyl));-   R² represents H or OH;-   R³ represents H;-   A represents C₁ alkylene or linear C₂ alkylene;-   B represents —Z—, —Z—N(H)— or —Z—O— (in which latter two groups, Z    is attached to the carbon atom bearing R² and R³, and represents C₁    alkylene or linear C₂ alkylene);-   G represents CH; and-   R⁴ is a single cyano group in the para-position relative to B,-   may be prepared by a process which comprises the steps of:-   (i) removal of the —SO₂R⁹ group from a compound of formula I in    which R¹ represents —S(O)₂R⁹, wherein R⁹ represents optionally    substituted phenyl, R⁴¹ to R⁴⁶ all represent H, G represents CH, A    and B both represent direct bonds, R² and R³ independently represent    H or C₁₋₆ alkyl and R⁴ is absent or represents one to three halo,    methyl, methoxy or nitro groups, especially 2- or 4-fluoro, 2- or    4-chloro, 4-bromo, 4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or    4-nitro, to provide a compound of formula II as hereinbefore    defined, in which R⁴¹ to R⁴⁶ all represent H, G represents CH, A and    B both represent direct bonds, R² and R³ independently represent H    or C₁₋₆ alkyl and R⁴ is absent or represents one to three halo,    methyl, methoxy or nitro groups, especially 2- or 4-fluoro, 2- or    4-chloro, 4-bromo, 4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or    4-nitro, for example using standard deprotection conditions (e.g. in    the presence of a standard deprotecting agent (such a hydrohalic    acid (e.g. HBr, especially concentrated aqueous HBr) or a reducing    agent such as LiAlH₄), at or above room temperature (e.g. at reflux)    with or without the presence of a solvent;-   (ii) reaction of the resultant compound of formula II with a    compound of formula III, as hereinbefore defined, in which R¹    represents straight- or branched-chain C₁₋₄ alkyl (e.g. C₁₋₃ alkyl,    such as methyl) terminated by C(O)R^(5a) or —N(H)C(O)OR^(10b), in    which R^(5a) and R^(10b) independently represent straight- or    branched-chain C₂₋₆ alkyl (e.g. C₃₋₅ alkyl, such butyl (e.g.    t-butyl)), to form a compound of formula I in which R¹ represents    straight- or branched-chain C₁₋₄ alkyl (e.g. C₁₋₃ alkyl, such as    methyl) terminated by C(O)R^(5a) or —N(H)C(O)OR^(10b), R^(5a) and    R^(10b) independently represent straight- or branched-chain C₂₋₆    alkyl (e.g. C₃₋₅ alkyl, such butyl (e.g. t-butyl)), R⁴¹ to R⁴⁶ all    represent H, G represents CH, A and B both represent a direct bond,    R² and R³ independently represent H or C₁₋₆ alkyl and R⁴ is absent    or represents one to three halo, methyl, methoxy or nitro groups,    especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo, 4-methyl,    2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro, for example under    conditions described hereinbefore (see e.g. process (a)), e.g. in    the presence of a suitable solvent (e.g. water, a lower alkyl    alcohol, acetonitrile, or mixtures thereof) and an appropriate base    (e.g. sodium bicarbonate or potassium carbonate);-   (iii) removal of the

-    fragment from the resultant compound of formula I to provide a    compound of formula VII in which R¹ represents straight- or    branched-chain C₁₋₄ alkyl (e.g. C₁₋₃ alkyl, such as methyl)    terminated by C(O)R^(5a) or —N(H)C(O)OR^(10b), R^(5a) and R^(10b)    independently represent straight- or branched-chain C₂₋₆ alkyl (e.g.    C₃₋₅ alkyl, such butyl (e.g. t-butyl)), and R⁴¹ to R⁴⁶ all represent    H, for example under appropriate deprotection conditions, such as    hydrogenation in the presence of a supported palladium catalyst    (e.g. Pd/C), for example at room temperature in the presence of a    suitable solvent (e.g. a lower alkyl alcohol, such as ethanol)); and-   (iv) reaction of the resultant compound of formula VII with a    compound of formula VIII as hereinbefore defined, in which R²    represents H or OH, R³ represents H, A represents C₁ alkylene or    linear C₂ alkylene, B represents —Z—, —Z—N(H)— or —Z—O— (in which    latter two groups, Z is attached to the carbon atom bearing R² and    R³, and represents C₁ alkylene or linear C₂ alkylene), G represents    CH and R⁴ is a single cyano group in the para-position relative to    B, and L² represents, for example, arenesulfonate (e.g.    toluenesulfonate), for example under conditions described    hereinbefore (see e.g. process (d)), such as at between room and    reflux temperature, in the presence of a suitable base (e.g.    potassium carbonate) and an appropriate organic solvent (e.g. a    lower alkyl alcohol, such as ethanol).

The skilled person will appreciate that, if desired, the above steps maybe performed in a different order to those that stated above, to providethe relevant compounds of formula I. For example, steps (iii) and (iv)may be carried out prior to steps (i) and (ii). Alternatively, steps (i)and (iii) (in either order) may be completed before steps (ii) and (iv)(in either order) are carried out. However, we prefer that the steps areperformed in the above-stated order.

The process of making the compounds of formula I from compounds offormulae XLVIII and XXIV (i.e. via compounds of formula XLVII) may havethe advantage that oxabispidine ring systems may be formed using fewersteps than methods described in the prior art, and, particularly, avoidsthe use of mercury-containing compounds (thereby eliminating theproduction of toxic, mercury-containing waste). This process offers aconvenient synthetic route to key oxabispidine compounds, and allowsdifferential protection at the nitrogen atoms.

Further, this process may have the advantage that compounds comprisingthe oxabispidine ring may be prepared in less time, more conveniently,and/or at a lower cost, than when prepared in processes described in theprior art.

Compounds of formulae III, V, VI, XI, XII, XIII, XVI, XVII, XVIII, XIX,XXI, XXII, XXIV, XXV, XXVII, XXVIII, XXIX, XXX, XXXA, XXXB, XXXC, XXXD,XXXE, XXXF, XXXG, XXXI, XXXII, XXXIIIA, XXXIIIB, XXXIVA, XXXIVB, XXXV,XXXVI, XLI, XLIII, XLIV and XLVI and derivatives thereof, are eithercommercially available, are known in the literature, or may be obtainedeither by analogy with the processes described herein, or byconventional synthetic procedures, in accordance with standardtechniques, from readily available starting materials using appropriatereagents and reaction conditions.

Substituents on the aryl (e.g. phenyl), and (if appropriate)heterocyclic, group(s) in compounds defined herein may be converted toother claimed substituents using techniques well known to those skilledin the art. For example, hydroxy may be converted to alkoxy, phenyl maybe halogenated to give halophenyl, nitro may be reduced to give amino,halo may be displaced by cyano, etc.

The skilled person will also appreciate that various standardsubstituent or functional group interconversions and transformationswithin certain compounds of formula I will provide other compounds offormulae I. For example, carbonyl may be reduced to hydroxy or alkylene,and hydroxy may be converted to halo.

The compounds of the invention may be isolated from their reactionmixtures using conventional techniques.

It will be appreciated by those skilled in the art that, in the processdescribed above, the functional groups of intermediate compounds may be,or may need to be, protected by protecting groups.

Functional groups which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl and diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl and alkylcarbonyl groups (e.g. methyl- andethylcarbonyl groups). Suitable protecting groups for amino includebenzyl, sulfonamido (e.g. benzenesulfonamido), tert-butyloxycarbonyl,9-fluorenyl-methoxycarbonyl or benzyloxycarbonyl. Suitable protectinggroups for amidino and guanidino include benzyloxycarbonyl. Suitableprotecting groups for carboxylic acid include C₁₋₆ alkyl or benzylesters.

The protection and deprotection of functional groups may take placebefore or after any of the reaction steps described hereinbefore.

Protecting groups may be removed in accordance with techniques which arewell known to those skilled in the art and as described hereinafter. Forexample, we have found that removal of an —SO₂R⁹ group from anoxabispidine ring may take place conveniently by employment of anappropriate strong acid, such as a hydrohalic acid (especially HBr) e.g.as described hereinbefore.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J. W. F. McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

Persons skilled in the art will appreciate that, in order to obtaincompounds of the invention in an alternative, and, on some occasions,more convenient, manner, the individual process steps mentioned hereinmay be performed in a different order, and/or the individual reactionsmay be performed at a different stage in the overall route (i.e.substituents may be added to and/or chemical transformations performedupon, different intermediates to those associated hereinbefore with aparticular reaction). This will depend inter alia on factors such as thenature of other functional groups present in a particular substrate, theavailability of key intermediates and the protecting group strategy (ifany) to be adopted. Clearly, the type of chemistry involved willinfluence the choice of reagent that is used in the said syntheticsteps, the need, and type, of protecting groups that are employed, andthe sequence for accomplishing the synthesis.

It will also be appreciated by those skilled in the art that, althoughcertain protected derivatives of compounds of formula I, which may bemade prior to a final deprotection stage, may not possesspharmacological activity as such, they may be administered parenterallyor orally and thereafter metabolised in the body to form compounds ofthe invention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. Moreover, certain compounds offormula I may act as prodrugs of other compounds of formula I.

All prodrugs of compounds of formula I are included within the scope ofthe invention.

Some of the intermediates referred to hereinbefore are novel. Accordingto a further aspect of the invention there is thus provided: (a) acompound of is formula II, as hereinbefore defined, or a protectedderivative thereof, optionally in the form of a salt and/or a solvate;(b) a compound of formula IV, as hereinbefore defined, or a protectedderivative thereof; (c) a compound of formula VII, as hereinbeforedefined, or a protected derivative thereof (provided that R¹ does notrepresent —S(O)₂R⁹, wherein R⁹ represents unsubstituted phenyl).Preferred compounds of formula VII include those in which R¹ does notrepresent C(O)OR⁷, in which R⁷ is tert-butyl; (d) a compound of formulaX, as hereinbefore defined, or a protected derivative thereof; (e) acompound of formula XIV, as hereinbefore defined, or a protectedderivative thereof; (f) a compound of formula XV, as hereinbeforedefined, or a protected derivative thereof; (g) a compound of formulaXX, as hereinbefore defined, or a protected derivative thereof; (h) acompound of formula XXIII, as hereinbefore defined, or a protectedderivative thereof, provided that L² does not represent iodo; (i) acompound of formula XXXIX, or a protected derivative thereof; and A) acompound of formula XLII, or a protected derivative thereof.

Preferred compounds of formula II include those in which:

-   R⁴¹ to R⁴⁶ all represent H;-   G represents CH;-   A represents a direct bond;-   B represents a direct bond;-   R² represents H or C₁₋₆ alkyl;-   R³ represents H or C₁₋₆ alkyl; and/or-   R⁴ is absent or represents one to three halo, methyl, methoxy or    nitro groups.

Particularly preferred compounds of formula II include those in which:

-   R² and R³ both represent H, and R⁴ is absent, optionally in the form    of a sulfate, hemisulfate or, especially, a hydrochloride (such as a    dihydrochloride) salt, which salt is optionally a hydrate (e.g. a    hemihydrate).

Preferred compounds of formula VII include those which are not:tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.

Preferred compounds of formula XLVII include those in which the group R¹and the group

are different, and as such include those compounds of formula XLVII inwhich:

-   R¹ represents —C(O)XR⁷, —C(O)N(R⁸)R^(5d) or —S(O)₂R⁹ (wherein X,    R^(5d), R⁷, R⁸ and R⁹ are as hereinbefore defined);-   R² and R³ do not together represent ═O when A represents a direct    bond.

Particularly preferred compounds of formula XLVII include those in which

-   R¹ represents —S(O)₂R⁹, wherein R⁹ represents aryl (such as phenyl,    particularly unsubstituted phenyl);-   G represents CH;-   A represents a direct bond;-   B represents a direct bond;-   R² represents H or C₁₋₆ alkyl;-   R³ represents H or C₁₋₆ alkyl;-   R⁴ is absent or represents one to three halo, methyl, methoxy or    nitro groups, especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo,    4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro.    Medical and Pharmaceutical Use

Compounds of the invention are useful because they possesspharmacological activity. They are therefore indicated aspharmaceuticals.

Thus, according to a further aspect of the invention there is providedthe compounds of the invention for use as pharmaceuticals.

In particular, the compounds of the invention exhibit myocardialelectrophysiological activity, for example as demonstrated in the testdescribed below.

The compounds of the invention are thus expected to be useful in boththe prophylaxis and the treatment of arrhythmias, and in particularatrial and ventricular arrhythmias.

The compounds of the invention are thus indicated in the treatment orprophylaxis of cardiac diseases, or in indications related to cardiacdiseases, in which arrhythmias are believed to play a major role,including ischaemic heart disease, sudden heart attack, myocardialinfarction, heart failure, cardiac surgery and thromboembolic events.

In the treatment of arrhythmias, compounds of the invention have beenfound to selectively delay cardiac repolarization, thus prolonging theQT interval, and, in particular, to exhibit class III activity. Althoughcompounds of the invention have been found to exhibit class III activityin particular, in the treatment of arrhythmias, their mode(s) ofactivity is/are not necessarily restricted to this class.

According to a further aspect of the invention, there is provided amethod of treatment of an arrhythmia which method comprisesadministration of a therapeutically effective amount of a compound ofthe invention to a person suffering from, or susceptible to, such acondition.

Pharmaceutical Preparations

The compounds of the invention will normally be administered orally,subcutaneously, intravenously, intraarterially, transdermally,intranasally, by inhalation, or by any other parenteral route, in theform of pharmaceutical preparations comprising the active ingredienteither as a free base or a non-toxic organic or inorganic acid additionsalt, in a pharmaceutically acceptable dosage form. Depending upon thedisorder and patient to be treated, as well as the route ofadministration, the compositions may be administered at varying doses.

The compounds of the invention may also be combined with any other drugsuseful in the treatment of arrhythmias and/or other cardiovasculardisorders.

According to a further aspect of the invention there is thus provided apharmaceutical formulation including a compound of the invention inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.

Suitable daily doses of the compounds of the invention in therapeutictreatment of humans are about 0.005 to 25.0 mg/kg body weight at oraladministration and about 0.005 to 10.0 mg/kg body weight at parenteraladministration. Preferable ranges of daily doses of the compounds of theinvention in therapeutic treatment of humans are about 0.005 to 10.0mg/kg body weight at oral administration and about 0.005 to 5.0 mg/kgbody weight at parenteral administration.

The compounds of the invention have the advantage that they areeffective against cardiac arrhythmias.

Compounds of the invention may also have the advantage that they may bemore efficacious than, be less toxic than, have a broader range ofactivity (including exhibiting any combination of class I, class II,class III and/or class IV activity (especially class I and/or class IVactivity in addition to class III activity)) than, be more potent than,be longer acting than, produce fewer side effects (including a lowerincidence of proarrhythmias such as torsades de pointes) than, be moreeasily absorbed than, or that they may have other useful pharmacologicalproperties over, compounds known in the prior art.

Biological Tests

Test A

Primary Electrophysiological Effects in Anaesthetised Guinea Pigs

Guinea pigs weighing between 660 and 1100 g were used. The animals werehoused for at least one week before the experiment and had free accessto food and tap water during that period.

Anaesthesia was induced by an intraperitoneal injection of pentobarbital(40 to 50 mg/kg) and catheters were introduced into one carotid artery(for blood pressure recording and blood sampling) and into one jugularvein (for is drug infusions). Needle electrodes were placed on the limbsfor recording of ECGs (lead II). A thermistor was placed in the rectumand the animal was placed on a heating pad, set to a rectal temperatureof between 37.5 and 38.5° C.

A tracheotomy was performed and the animal was artificially ventilatedwith room air by use of a small animal ventilator, set to keep bloodgases within the normal range for the species. In order to reduceautonomic influences both vagi were cut in the neck, and 0.5 mg/kg ofpropranolol was given intravenously, 15 minutes before the start of theexperiment.

The left ventricular epicardium was exposed by a left-sided thoracotomy,and a custom-designed suction electrode for recording of the monophasicaction potential (MAP) was applied to the left ventricular free wall.The electrode was kept in position as long as an acceptable signal couldbe recorded, otherwise it was moved to a new position. A bipolarelectrode for pacing was clipped to the left atrium. Pacing (2 msduration, twice the diastolic threshold) was performed with acustom-made constant current stimulator. The heart was paced at afrequency just above the normal sinus rate during 1 minute every fifthminute throughout the study.

The blood pressure, the MAP signal and the lead II ECG were recorded ona Mingograph ink-jet recorder (Siemens-Elema, Sweden). All signals werecollected (sampling frequency 1000 Hz) on a PC during the last 10seconds of each pacing sequence and the last 10 seconds of the followingminute of sinus rhythm. The signals were processed using a custom-madeprogram developed for acquisition and analysis of physiological signalsmeasured in experimental animals (see Axenborg and Hirsch, Comput.Methods Programs Biomed. 41, 55 (1993)).

The test procedure consisted of taking two basal control recordings, 5minutes apart, during both pacing and sinus rhythm. After the secondcontrol recording, the first dose of the test substance was infused in avolume of 0.2 mL into the jugular vein catheter for 30 seconds. Threeminutes later, pacing was started and a new recording was made. Fiveminutes after the previous dose, the next dose of test substance wasadministered. Six to ten consecutive doses were given during eachexperiment.

Data Analysis

Of the numerous variables measured in this analysis, three were selectedas the most important for comparison and selection of active compounds.The three variables selected were the MAP duration at 75 percentrepolarization during pacing, the atrio-ventricular (AV) conduction time(defined as the interval between the atrial pace pulse and the start ofthe ventricular MAP) during pacing, and the heart rate (defined as theRR interval during sinus rhythm). Systolic and diastolic blood pressurewere measured in order to judge the haemodynamnic status of theanaesthetised animal. Further, the ECG was checked for arrhythmiasand/or morphological changes.

The mean of the two control recordings was set to zero and the effectsrecorded after consecutive doses of test substance were expressed aspercentage changes from this value. By plotting these percentage valuesagainst the cumulative dose administered before each recording, it waspossible to construct dose-response curves. In this way, each experimentgenerated three dose-response curves, one for SLAP duration, one forAV-conduction time and one for the sinus frequency (RR interval). A meancurve of all experiments performed with a test substance was calculated,and is potency values were derived from the mean curve. Alldose-response curves in these experiments were constructed by linearconnection of the data points obtained. The cumulative dose prolongingthe MAP duration by 10% from the baseline was used as an index to assessthe class III electrophysiological potency of the agent underinvestigation (D₁₀).

Test B

Glucocorticoid-treated Mouse Fibroblasts as a Model to Detect Blockersof the Delayed Rectifier K Current

IC50 for K channel blockade was determined using a microtitre platebased screen method, based on membrane potential changes ofglucocorticoid-treated mouse fibroblasts. The membrane potential ofglucocorticoid-treated mouse fibroblasts was measured using fluorescenceof the bisoxonol dye DiBac₄₍₃₎, which could be reliably detected using afluorescence laser imaging plate reader (FLIPR). Expression of a delayedrectifier potassium channel was induced in mouse fibroblasts by 24 hoursexposure to the glucocorticoide dexamehasone (5 μM). Blockade of thesepotassium channels depolarised the fibroblasts, resulting in increasedfluorescence of DiBac₄₍₃₎.

Mouse ltk fibroblasts (L-cells) were purchased from American TypeCulture Collection (ATCC, Manassa, Va.), and were cultured in Dulbeccosmodified eagle medium supplemented with fetal calf serum (5% vol/vol),penicillin (500 units/in L), streptomycin (500 μg/mL) andL-alanine-L-glutamine (0.862 mg/mL). The cells were passaged every 3-4days using trypsin (0.5 mg/mL in calcium-free phosphate buffered saline,Gibco BRL). Three days prior to experiments, cell-suspension waspipetted out into clear-bottom, black plastic, 96-well plates (Costar)at 25 000 cells/well.

The fluorescence probe DiBac₄₍₃₎ (DiBac Molecular probes) was used tomeasure membrane potential. DiBacl₄₍₃₎ maximally absorbs at 488 nM andemits at 513 nM. DiBac₄₍₃₎ is a bisoxonol, and thus is negativelycharged at pH 7. Due to its negative charge, the distribution ofDiBac₄₍₃₎ across the membrane is dependent upon the transmembranepotential: if the cell depolarizes (i.e. the cell interior becomes lessnegative relative to cell exterior), the DiBac₄₍₃₎ concentration insidethe cell increases, due to electrostatic forces. Once inside the cell,DiBac₄₍₃₎ molecules can bind to lipids and proteins, which causes anincrease in fluorescence emission. Thus, a depolarization will bereflected by an increase in DiBac₄₍₃₎ fluorescence. The change inDiBac₄₍₃₎ fluorescence was detected by a FLIPR.

Prior to each experiment, the cells were washed 4 times inphosphate-buffered saline (PBS) to remove all culture media. The cellswere then treated with 5 μM DiBac₄₍₃₎ (in 180 μL of PBS) at 35° C. Oncea stable fluorescence was reached (usually after 10 min), 20 μL of thetest substance was added, using FLIPR's internal 96 well pipettingsystem. Fluorescence measurements were then taken every 20 sec for afurther 10 min. All experiments were carried out at 35° C., due to thehigh temperature sensitivity of both delayed rectifier potassium channelconductance and DiBac₄₍₃₎ fluorescence. Test substances were prepared ina second 96 well plate, in PBS containing 5 μM DiBac₄₍₃₎. Theconcentration of substance prepared was 10 times that of the desiredconcentration in the experiment as an additional 1:10 dilution occurredduring addition of substance during the experiment. Dofetilide (10 μM)was used as a positive control, i.e. to determine the maximum increasein fluorescence.

Curve-fitting, used to determine the IC50 values, was performed with theGraphpad Prism program (Graphpad Software Inc., San Diego, Calif.).

Test C

Metabolic Stability of Test Compounds

An in vitro screen was set up to determine the metabolic stability ofthe compounds of the invention.

The hepatic S-9 fraction from dog, man, rabbit and rat with NADPH asco-factor was used. The assay conditions were as follows: S-9 (3 mg/mL),NADPH (0.83 mM), Tris-HCl buffer (50 mM) at pH 7.4 and 10 μM of testcompound.

The reaction was started by addition of test compound and terminatedafter 0, 1, 5, 15 and 30 minutes by raising the pH in the sample toabove 10 (NaOH; 1 mM). After solvent extraction, the concentration oftest compound was measured against an internal standard by LC(fluorescence/UV detection).

The percentage of test compound remaining after 30 minutes (and thust_(1/2)) was calculated and used as a measure for metabolic stability.

The invention is illustrated by way of the following examples.

EXAMPLES

General Experimental Procedures

Mass spectra were recorded on one of the following instruments: aPerkin-Elmer SciX API 150ex spectrometer; a VG Quattro II triplequadrupole; a VG Platform II single quadrupole; or a Micromass PlatformLCZ single quadrupole mass spectrometer (the latter three instrumentswere equipped with a pneumatically assisted electrospray interface(LC-MS)). ¹H NMR and ¹³C NMR measurements were performed on a BRUKER ACP300 and Varian 300, 400 and 500 spectrometers, operating at ¹Hfrequencies of 300, 400 and 500 MHz respectively, and at ¹³C frequenciesof 75.5, 100.6 and 125.7 MHz respectively. Alternatively, ¹³C NMRmeasurements were performed on a BRUKER ACE 200 spectrometer at afrequency of 50.3 MHz.

Rotamers may or may not be denoted in spectra depending upon ease ofinterpretation of spectra. Unless otherwise stated, chemical shifts aregiven in ppm with the solvent as internal standard.

Synthesis of Intermediates

The following intermediates were not commercially available, and weretherefore prepared by the methods described below.

Preparation A

tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylatehydrochloride (i) 2,6-Bis(iodomethyl)-4-(phenylsulfonyl)morpholine

The sub-title compound was prepared according to both of the followingtwo methods:

-   (a) To a stirred mixture of water (835 mL), chloroform (1.25 L) and    iodine (418.7 g, 1.65 mol) under an inert atmosphere (N₂) was added,    portion-wise over a period of 30 min,    2,6-bis[(acetoxymercuri)methyl]-4-(phenylsulfonyl)morpholine    (prepared as described in Chem. Ber. 96, 2827 (1963); 421.3 g, 0.55    mol), during which time the reaction mixture was warmed to reflux.    After addition was complete, reflux was continued overnight before    the mixture was allowed to cool to room temperature. The mixture was    filtered and the chloroform layer separated. A saturated aqueous    solution of Na₂S₂O₃ was added to the organic solution until the    iodine colour disappeared. The organic layer was again separated,    then dried (Na₂SO₄), filtered and concentrated in vacuo to yield    279.9 g (100%) of the sub-title compound as a light yellow    crystalline solid. HPLC analysis indicated this product to be    composed of 46% cis-isomer and 54% trans-isomer.-   (b) Acetonitrile (50 mL) and then ether (150 mL) were added to    triphenylphosphine (20.1 g, 77 mmol). Imidazole (5.24 g, 77 mmol)    was added and the solution cooled to 5° C. Iodine (19.5 g, 77 mmol)    was added, causing the temperature to rise to 17° C. A solution of    2,6-bis-(hydroxymethyl)-4-(phenylsulfonyl)morpholine (Preparation L;    10.65 g, 37 mmol) in acetonitrile (50 mL) was added and the reaction    stirred at room temperature for 22 hours. Aqueous sodium thiosulfate    (5%, 100 mL) was added and the layers separated. The organic phase    was washed with dilute sulfuric acid (100 mL) and then was    concentrated under reduced pressure. The residue was purified by    chromatography over silica (200 g), eluting with dichloromethane    (1.5 L), to give a yellow oil. This was triturated with ether to    give the title compound as a yellow solid (a 1:1 mixture of cis- and    trans-isomers; 6.1 g, 37%). The ether wash contained impure product    (1.90 g).

API MS: m/z=508 [C₁₂H₁₅I₂NO₃S+H]⁺.

(ii) 3-Benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane

A mixture of benzylamine. (173.3 g, 1.62 mol), cis- andtrans-2,6-bis(iodomethyl)-4-(phenylsulfonyl)morpholine (from step (i)(a)above; 275 g, 0.54 mol), and sodium hydrogencarbonate (182.2 g, 2.17mol) in acetonitrile (13.5 L) was refluxed for 24 h. After this time, analiquot was removed and diluted with ethyl acetate. HPLC analysis ofthis sample indicated that approximately 9% of the cis-isomer of thestarting material remained unreacted. Reflux was continued for a further6 h, but this gave no change in the percentage of unreacted startingmaterial (as indicated by HPLC). The reaction was then allowed to coolto rt before the mixture was filtered and the filtrate concentrated invacuo. The resulting crude product was partitioned betweendichloromethane and 0.5 N NaOH solution. The organic layer wasseparated, washed with brine, dried (Na₂SO₄), filtered and thenconcentrated in vacuo to afford a mixture of oil and crystals. Thismixture was slurried in toluene (300 mL) and the crystalline productcollected by filtration. The filter cake of crystals was rinsed withcold toluene (100 mL), and then dried in a vacuum oven overnight (40°C., 13.3 Pa (0.1 mmHg)) to give 61.7 g (31.9% yield, 72.8% conversion ofthe cis-isomer) of the sub-title compound.

API MS: m/z=359 [C₁₉H₂₂N₂O₃S+H]⁺.

(iii) 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride

To a mixture of anhydrous THF (1.1 L) and pellets of LiAlH₄ (48.5 g, 1.2mol) under an inert atmosphere (N₂) was added3-benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane (fromstep (ii) above; 61.7 g, 0.17 mol) in portions over a 30 min period. Themixture was refluxed for 48 h before being cooled to −10° C. The cooledmixture was then treated sequentially (and cautiously) with water (45.8mL), 15% is NaOH solution (45.8 mL) and then water (137.4 mL) again. Theresulting mixture was filtered through Celite® and the filtrate setaside. The inorganic-salts from the filter cake were transferred to abeaker and stirred with ethyl acetate (1 L) for 30 min. This slurry wasthen filtered through Celite® again. The two filtrates were combined andthen concentrated in vacuo to afford an oil (32.2 g). This oil wasdissolved in methanol (120 mL) and treated with a solution of HCl in IPA(100 mL), after which the solution pH was checked for acidity. Afterstanding for 24 h, a crop of crystals was collected by filtration anddried to a constant weight of 26.8 g. A second crop of crystals (7 g)was later obtained by crystallisation of the remaining crude productfrom IPA, giving a total yield of 33.8 g (68%) of the sub-titlecompound.

¹H NMR (CD₃OD+4 drops D₂O): δ 2.70 (br d, 2H), 3.09 (d, 2H), 3.47 (br s,4H), 3.60 (s, 2H), 4.12 (br s, 2H), 7.30-7.45 (m, 5H).

API MS: m/z=219 [C₁₃H₁₈N₂O+H]⁺.

(iv) tert-Butyl7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

A mixture of water (400 mL), dichloromethane (400 mL), sodiumhydrogencarbonate (40.3 g, 0.48 mol) and3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (from step(iii) above; 33.7 g, 0.12 mol) was stirred rapidly for 10 min beforedi-tert-butyl dicarbonate (27.8 g, 0.13 mol) was added in portions.After addition was complete, the reaction was stirred for a further 2 h.The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated in vacuo to afford 39.6 g of an off-white crystallinesolid. This material was used directly in the next step without anyfurther purification.

¹H NMR (CD₃OD): δ 1.5 (s, 9H), 2.42 (br t, 2H), 2.88 (d, 2H), 3.18-3.28(m, 2H), 3.38 (d, 2H), 3.80 (br d, 2H), 4.00 (d, 2H), 7.16-7.38 (m, 5H).

(v) tert-Butyl7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride

A solution of tert-butyl7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (39.5 g, 0.12mol) in ethyl acetate (200 mL) was cooled to −10° C. under an inertatmosphere (N₂). A solution of HCl in diethyl ether (1 M) was added overthe course of 1 h, during which time a precipitate formed. Afteraddition was complete, the resulting mixture was stirred for a further 1h before the crystalline precipitate was collected by filtration anddried in a vacuum oven (40° C., 13.3 Pa (0.1 mmHg)). This gave 42.6 g(100% from the compound of step (iii) above) of the sub-title compoundas an off-white crystalline material.

API MS: m/z=219 [C₁₈H₂₆N₂O₃−C₅H₉O₂]⁺.

(vi) tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylatehydrochloride

A mixture of tert-butyl7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride(from step (vi) above; 42.6 g, 0.12 mol), 10% palladium on carbon (2.5g) and methanol (450 mL) was subjected to hydrogenation at atmosphericpressure. Once the reaction was complete (as indicated by tlc), themixture was filtered and the filtrate concentrated in vacuo to yield31.6 g of an off-white crystalline product. This crude product wasdissolved in hot acetonitrile (450 mL), filtered and the filtratediluted with ethyl acetate (450 mL). After being allowed to stand at rtfor 6 h, the mixture was filtered to remove the first crop ofcrystallised product (19.8 g). The mother liquor was then concentratedto near dryness to give a residue that was dissolved in hot acetonitrile(150 mL). Ethyl acetate (150 mL) was added to this solution and themixture allowed is to stand at room temperature overnight. A second cropof crystalline product (8.7 g) was then collected by filtration, and wasfound to have an identical ¹H NMR spectrum and melting point to thefirst crop. The combined yield of title compound was therefore 28.5 g(89%).

m.p.=207-208° C.

Preparation B

4-{[(2S)-2-Hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]-oxy}benzonitrile(i) 4-[(2S)-Oxiranylmethoxy]benzonitrile

Potassium carbonate (414 g) and (R)-(−)-epiclorohydrin (800 mL) wereadded to a stirred solution of p-cyanophenol (238 g) in 2.0 L MeCN andthe reaction mixture was refluxed under an inert atmosphere for 2 h. Thehot solution was filtered and the filtrate concentrated, giving a clearoil which was crystallised from di-iso-propyl ether giving the productin 90% yield.

(ii) tert-Butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

A mixture of tert-butyl9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (prepared in ananalogous fashion to the compound of Preparation A(vi) above; 0.72 g,3.2 mmol) and 4-[(2S)-oxiranylmethoxy]benzonitrile (from step (i) above;0.56 g, 3.2 mmol) in IPA/water (11 mL of 10:1) was stirred at 60° C. for18 h. The solvent was then evaporated to give 1.3 g (100%) of thesub-title compound, which was used in the next step without furtherpurification.

(iii)4-{[(2S)-2-Hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]-oxy}benzonitrile

A solution of tert-butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(from step (ii) above; 1.0 g, 2.47 mmol) in ethyl acetate (13 mL) wascooled to 0° C. Ethyl acetate (26 mL) saturated with gaseous HCl wasadded, and the mixture stirred for 4 h at rt. The solvent was removed invacuo before MeCN (25 mL), water (1.3 mL) and K₂CO₃ (2.0 g) were added.The resulting mixture was stirred overnight before CHCl₃ was added, andthe mixture filtered through Celite®. The filtrate was concentrated invacuo to give 682 mg (91%) of the title compound.

Preparation C

4-{[3-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}benzonitrile(i) 4-[(3-Hydroxypropyl)amino]benzonitrile

A mixture of 4-fluorobenzoaitrile (12.0 g, 99.1 mmol) and3-amino-1-propanol (59.6 g, 793 mmol) was stirred at 80° C. under aninert atmosphere for 3 hours before water (150 mL) was added. Themixture was allowed to cool to rt, and was then extracted with diethylether. The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated in vacuo to yield 17 g (97%) of the title compound as anoil that crystallised upon standing.

(ii) 3-(4-Cyanoanilino)propyl 4-methylbenzenesulfonate

A cooled (0° C.) solution of 4-[(3-hydroxypropyl)amino]benzonitrile(from step (i) above; 17 g, 96.5 mmol) in dry MeCN (195 mL) was treatedwith triethylamine (9.8 g, 96.5 mmol) and then p-toluenesulfonylchloride (20.2 g, 106 mmol). The mixture was stirred at 0° C. for 90minutes before being concentrated in vacuo. Water (200 mL) was added tothe residue, and the aqueous solution was extracted with DCM. Theorganic phase was dried (Na₂SO₄), filtered and concentrated in vacuo.The resulting residue was purified by crystallisation from iso-propanolto yield 24.6 g (77%) of the sub-title compound.

(iii) tert-Butyl7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate

The hydrochloride salt of tert-butyl9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from PreparationA(vi) above; 1.1 g, 4.15 mmol) was mixed with MeCN (46 mL), water (2.5mL) and K₂CO₃ (3.5 g, 25 mmol). The mixture was stirred for 4 h beforeCHCl₃ was added and the mixture was filtered through Celite®. Thefiltrate was concentrated in vacuo to give 0.933 g of the free base.This was then mixed with 3-(4-cyanoanilino)propyl4-methylbenzenesulfonate (from step (ii) above; 2.1 g, 6.2 mmol) andK₂CO₃ (0.86 g, 6.2 mmol) in MeCN (18 mL). The resulting mixture wasstirred overnight at 60° C. before being concentrated in vacuo. Theresidue was treated with DCM (250 mL) and 1 M NaOH (50 mL). The layerswere separated and the DCM layer washed twice with aqueous NaHCO₃,before being dried (Na₂SO₄) and concentrated in vacuo. The product waspurified by flash chromatography, eluting with a gradient oftoluene:ethyl acetate:triethylamine (2:1:0 to 1000:1000:1), to give 1.47g (91%) of the sub-title compound.

(iv)4-{[3-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}-benzonitrile

The title compound was obtained in 96% yield according to the proceduredescribed in Preparation B(iii) above, using tert-butyl7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(from step (iii) above) in place of tert-butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.

Preparation D

4-[2-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethoxy]benzonitrile (i)4-(2-Bromoethoxy)benzonitrile

A mixture of 4-cyanophenol (35.7 g, 0.3 mol), K₂CO₃ (41.4 g, 0.3 mol)and 1,2-dibromoethane (561 g, 3.0 mol) in MeCN (450 mL) was stirredunder reflux overnight. The mixture was filtered and evaporated to give30.2 g (45%) of the sub-title compound, which was used without furtherpurification.

(ii) tert-Butyl7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate

The sub-title compound was prepared in 85% yield according to theprocedure described in Preparation C(iii) above, using4-(2-bromoethoxy)-benzonitrile (0.8 g, 3.5 mmol, 1.03 eq.) andtriethylamine (1.5 eq.) in place of 3-(4-cyanoanilino)propyl4-methylbenzenesulfonate, and K₂CO₃, respectively.

(iii) 4-[2-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethoxy]benzonitrile

The title compound was obtained in 95% yield according to the proceduredescribed in Preparation B(iii) above, using tert-butyl7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(from step (ii) above) in place of tert-butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.

Preparation E

4-[3-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propoxy]benzonitrile (i)4-(3-Bromopropoxy)benzonitrile

1,3-Dibromopropane (1.02 L, 10 mol) was added to a stirred suspension ofp-cyanophenol (238 g, 2 mol), K₂CO₃ (276.4 g, 2 mol) in MeCN (2.7 L).The reaction mixture was refluxed for 4 h, filtered and concentrated.The residue was recrystallised from iso-propyl ether to give thesub-title compound in a 69% yield.

(ii) tert-Butyl7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate

The sub-title compound was prepared in 97% yield according to theprocedure described in Preparation C(iii) above, using4-(3-bromo-propoxy)benzonitrile (from step (i) above) in place of3-(4-cyanoanilino)-propyl 4-methylbenzenesulfonate.

(iii) 4-[3-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propoxy]benzonitrile

The title compound was obtained in 90% yield according to the proceduredescribed in Preparation B(iii) above, using tert-butyl7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(from step (ii) above) in place of tert-butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.

Preparation F

4-[2-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethoxy]isophthalonitrile (i)4-(2-Bromoethoxy)isophthalonitrile

The sub-title compound was prepared in 64% yield according to theprocedure described in Preparation D(i) above, using4-hydroxyisophthalonitrile in place of 4-cyanophenol.

(ii) tert-Butyl7-[2-(2,4-dicyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo-20[3.3.1]nonane-3-carboxylate

The sub-title compound was prepared in 62.7% yield according to theprocedure described in Preparation C(iii) above, using4-(2-bromoethoxy)-isophthalonitrile (from step (i) above) in place of3-(4-cyanoanilino)propyl 4-methylbenzenesulfonate.

(iii)4-[2-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethoxy]isophthalonitrile

The title compound was obtained according to the procedure described inPreparation B(iii) above, using tert-butyl7-[2-(2,4-dicyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(from step (ii) above) in place of tert-butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.

Preparation G

4-[4-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (i)4-(3-Butenyl)benzonitrile

Magnesium (4.2 g, 173 mmol) was activated by washing with dilute HCl,water and acetone and was then dried in vacuo. ZnBr₂ (37 g, 165 mmol)was sublimed under reduced pressure (approx. 5-20 mmHg) by gentleheating in a glovebox. The glovebox was used as it was extremely humidin the lab. Mg and ZnBr₂ were mixed in a dry 3-necked flask under N₂ anddry THF (30 mL) was added. 4-Bromo-1-butene (25.1 g, 186 mmol) dissolvedin dry THF (175 mL) was added dropwise to the Mg/ZBr₂ slurry and, duringthe addition, the reaction mixture turned greyish and then black. Someheat was also evolved (>40° C.). After complete addition, the mixturewas heated to 50° C. overnight. 4-Bromobenzonitrile (30.5 g, 167 mmol)was co-evaporated with toluene twice and was then dissolved in dry THF(250 ml) together with Pd(PPh₃)₄ (5 g, 4.3 mmol, 2.5 mole). The slurrywas added to the Grignard reagent and the reaction mixture was stirredat room-temperature overnight. HCl (500 mL, 3 M) was added dropwise tothe reaction mixture, and the resulting solution was extracted withether (1000+3×500 mL), the combined ether solutions were washed withNaHCO₃ (satd. 3×250 mL), dried, filtered and evaporated. The crudeproduct (29.7 g) was subjected to Dry-Flash chromatography (diameter 12cm, height 5 cm, heptane:EtOAc (99:1 to 90:10)) to give 21.2 g of thesub-title compound contaminated with 4-bromobenzonitrile (about 20%).This material was used in the next step.

(ii) 4-(4-Hydroxybutyl)benzonitrile

4-(3-Butenyl)benzonitrile (from step (i) above, 10.8 g, 69 mmol) wasdissolved in dry THF (140 mL) and was cooled to 0° C. BH₃-MeS complex(20 mL, 2 M) was added dropwise over 45 minutes at 0° C. and, after 7hours, water (70 mL) and NaBO₃-4H₂O (25 g) were added and the mixturewas stirred overnight before dilution with ether (700 mL) and brine(satd., 250 mL). After separation, the aqueous phase was extracted withether (2×200 mL) and the combined extracts were dried, filtered andevaporated to give crude sub-title compound. Purification by flashchromatography on SiO₂ (300 g) with heptane:EtOAc (3:1 to 1:1) gave thesub-title compound (6.99 g)

(iii) 4-(4-Cyanophenyl)butyl methanesulfonate

Methanesulfonyl chloride (2.32 mL, 30 in mmol) was added to a cooled (0°C.), stirred solution of 4-(4-hydroxybutyl)benzonitrile (from step (ii)above, 5.2 g, 29.7 mmol) and triethylamine (4.35 mL) in dichloromethane(50 mL). The resulting, mixture was stirred for 4 h before water (150mL) was added, and the organic layer separated, dried and concentratedto give the sub-title compound. This product was used directly in thenext step without further purification.

(iv) tert-Butyl7-[4-(4-Cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate

The sub-title compound was prepared in 69.3% yield according to theprocedure described in Preparation C(iii) above, using4-(4-cyanophenyl)-butyl methanesulfonate (from step (iii) above) inplace of 3-(4-cyanoanilino)propyl 4-methylbenzenesulfonate.

(v) 4-[4(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile

The title compound was obtained in 88% yield according to the proceduredescribed in Preparation B(iii) above, using tert-butyl7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(from step (iv) above) in place of tert-butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.

Preparation H

4-[1-(3,4-Dimethoxyphenoxy)-4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile(i) 4-[1-(3,4-Dimethoxyphenoxy)-3-butenyl]benzonitrile

A cooled (0° C.) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (14.6 g,84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, 125.4 mmol) in toluene (500mL) was treated with tributylphosphine (32.14 mL of 97% purity, 25.6 g,126.4 mmol), followed by 1,1′-(azodicarbonyl)dipiperidine (31.8 g,126.4-mmol). After addition was complete, the reaction mixture thickenedand the temperature rose to 15° C. Additional toluene was added (500mL), and the mixture stirred at rt overnight. The precipitate oftributylphosphine oxide was then removed by filtration and the filtrateconcentrated in vacuo to give 65.8 g of crude product. This was purifiedby chromatography on silica gel, eluting with toluene:methanol (98:2),to yield 17.9 g of the sub-title compound.

(ii) 4-[1-(3,4-Dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile

Borane-methyl sulfide complex (2 M in ether, 11 mL, 22 mmol) was addeddropwise to a cooled (−5° C.) solution of4-[1-(3,4-dimethoxyphenoxy)-3-butenyl]benzonitrile (from step (i) above;17.6 g, 56.8 mmol) in dry THF (15 mL) over a period of 15 minutes(during which time the reaction temperature rose to 0° C.). Theresulting mixture was stirred at between 0 and 10° C. for 1.5 h, beforebeing allowed to warm to rt. Stirring was continued for a further 3.5 hat this temperature before water (22 mL) and sodium perboratetetrahydrate (11 g, 66 mmol) were added. The biphasic in mixture wasstirred for 2 h at rt before the water layer was separated and extractedwith ether. The combined organic layers were washed with brine, driedand concentrated in vacuo. The resulting residue was purified bychromatography on silica gel, eluting with IPA:ethyl acetate:heptane(5:25:70) to yield 14.5 g (77%) of the sub-title compound.

(iii) 4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate

A solution of methanesulfonyl chloride (3.4 mL, 5.0 g, 44 mmol) in DCM(15 mL) was added slowly to a cooled (−5° C.) mixture of4-[1-(3,4-dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile (from step (ii)above; 11 g, 34 mmol) and triethylamine (7 mL, 5.2 g, 50.6 mmol) in DCM(50 mL), during which addition the temperature did not rise above 2° C.Stirring was continued at between 0 and 5° C. for a further 2 h beforewater was added. The resulting organic layer was separated, and washedwith water, separated again and then dried to give the sub-titlecompound in 100% yield.

(iv) tert-Butyl7-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

The sub-title compound was prepared in 82% yield according to theprocedure described in Preparation C(iii) above, using4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate (fromstep (iii) above) in place of 3-(4-cyanoanilino)propyl4-methylbenzenesulfonate.

(v)4-[1-(3,4-Dimethoxyphenoxy)-4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile

The title compound was obtained in quantitative yield according to theprocedure described in Preparation B(iii) above, using tert-butyl7-[4-(4-cyanophenyl)-4-(3,4-dirnethoxyphenoxy)butyl]-9-oxa-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate(from step (iv) above) in place of tert-butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate.

Preparation I

4-{[3-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]sulfonyl}benzonitrile(i) 4-[(3-Bromopropyl)sulfanyl]benzonitrile

A mixture of 4-cyanothiophenol (20.8 g, 154 mmol), 1,3-dibromopropane(155 g, 0.77 mol) and K₂CO₃ (21.3 g, 154 mmol) in MeCN (300 mL) wasrefluxed overnight. Filtration and evaporation of the solvent gave abrown oil that crystallised when treated with EtOH. The crystals wereisolated by filtration to give the sub-title compound (24.5 g, 62%).

(ii) 4-[(3-Bromopropyl)sulfonyl]benzonitrile

3-Chloroperoxybenzoic acid (44.9 g of 70%, 182 mmol) was added slowly toa cooled (0° C.) solution of 4-[(3-bromopropyl)sulfanyl]benzonitrile(from step (i) above; 23.4 g, 91 mmol) in DCM (250 mL). The mixture wasthen stirred at rt overnight, and the resulting precipitate filteredoff. The filtrate was concentrated in vacuo to give a residue that wasshown (by NMR analysis) to contain 25% sulfoxide in addition to thedesired product. The residue was redissolved in DCM (250 mL), additional3-chloroperoxybenzoic acid (5.6 g of 70%, 23 mmol) added, and themixture stirred for 30 min. Dimethylsulfoxide (20 mmol) was added todestroy excess mCPBA before the DCM solution was washed with aqueousNaHCO₃, separated, dried and concentrated in vacuo. This gave thesub-title compound in 76% yield.

(iii) tert-Butyl7-{3-[(4-cyanophenyl)sulfonyl]propyl}-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

The sub-title compound was prepared in 64% yield according to theprocedure described in Preparation C(iii) above, using4-[(3-bromopropyl)sulfonyl]benzonitrile (from step (ii) above) in placeof 3-(4-cyanoanilino)propyl 4-methylbenzenesulfonate.

(iv)4-{[3-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]sulfonyl}-benzonitrile

The title compound was obtained in 84% yield according to the proceduredescribed in Preparation B(iii) above, using tert-butyl7-{3-[(4-cyanophenyl)sulfonyl]propyl}-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(from step (iii) above) in place of tert-butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.

Preparation J

tert-Butyl(1S)-2-(4-cyanophenoxy)-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)ethylcarbamate(i) 4-(2-Oxiranylmethoxy)benzonitrile

The sub-title compound was prepared in 75% yield according to theprocedure described in Preparation B(i) above, using epichlorohydrin inplace of (R)-(−)-epichlorohydrin.

(ii) 4-[(3-Amino-2-hydroxypropyl)oxy]benzonitrile

4-(Oxiranylmethoxy)benzonitrile (from step (i) above; 100 g, 0.57 mol)was added to a mixture of concentrated aqueous ammonium hydroxide (500mL) and iso-propanol (300 mL). The resulting slurry was stirred at roomtemperature for 3 days. The reaction mixture was filtered to remove theinsoluble by-product, and the filtrate was concentrated in vacuo to givea crude product, which was crystallised from acetonitrile to yield 50 g(46%) of the sub-title compound.

(iii) tert-Butyl 3-(4-cyanophenoxy)-2-hydroxypropylcarbamate

A cooled (0° C.) solution of4-[(3-amino-2-hydroxypropyl)oxy]benzonitrile (from step (ii) above; 44.6g, 0.23 mol) in THF:H₂O (1.5 L of 1:1) was treated with di-tert-butyldicarbonate (53 g, 0.24 mol). The mixture was stirred at rt overnight,after which NaCl was added and the resulting organic layer separated.The water layer was extracted with ether and the combined organics weredried and concentrated in vacuo. The resulting oil (70 g) was filteredthrough a plug of silica, and then crystallised from diethylether:di-iso-propyl ether to yield 50 g of the sub-title compound.

(iv) 2-[(tert-Butoxycarbonyl)amino]-1-[(4-cyanophenoxy)methyl]ethylmethanesulfonate

Methanesulfonyl chloride (22.3 g 0.195 mol) was added over the course of1.5 hours to a cooled (0° C.) solution of tert-butyl3-(4-cyano-phenoxy)-2-hydroxypropylcarbamate (from step (iii) above;51.2 g, 0.177 mol) and 4-(dimethylamino)pyridine (1.3 g, 10.6 mmol) inpyridine (250 mL), kept under an inert atmosphere. The reaction mixturewas stirred for 2 h at rt before water and DCM were added. The organiclayer was separated, washed with water, dried (MgSO₄) and concentratedin vacuo to yield 68.1 g (100%) of the sub-title compound.

(v) tert-Butyl 2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate

A cooled (0° C.) solution of2-[(tert-butoxycarbonyl)amino]-1-[(4-cyanophenoxy)methyl]ethylmethanesulfonate (from step (iv) above; 30.6 g, 82.6 mmol) andtetrabutylammonium hydrogensulfate (3 g, 8.8 mmol) in DCM (100 mL) wastreated with 50 wt. % aqueous NaOH (60 mL) under an inert atmosphere.The resulting mixture was stirred, and the temperature was slowlyallowed to rise to rt over for 4 h, and then extracted with ether. Theorganic layer was washed with water and concentrated in vacuo to give aresidue that was purified by column chromatography (dichloromethaneeluent). Crystallisation from diethyl ether:di-iso-propyl ether gave thesub-title compound in quantitative yield.

(vi) tert-Butyl (2S)-2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate

The sub-title compound was prepared according to the proceduresdescribed in steps (i) to (v) above for the synthesis of tert-butyl2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate, but using(S)-(+)-epichlorohydrin in place of epichlorohydrin in step (i).

(vii) 3-Benzyl-7-(tert-butyl)9-oxa-3,7-diazabicyclo[3.3.1]nonane-3,7-dicarboxylate

The hydrochloride salt of tert-butyl9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from PreparationA(vi) above; 2.17 g, 8.2 mmol) was dissolved in CHCl₃ (25 mL) and themixture was cooled to 0° C. Triethylamine (2.1 g, 20.6 mmol) was added,followed by N-(benzyloxycarbonyloxy)succinimide (2.24 g. 9.0 mmol), andthe mixture stirred at rt for 24 h. The reaction mixture was washed withwater (4×15 mL), before the organic layer was separated, dried (MgSO₄)and concentrated in vacuo. This gave the sub-tide compound (4.4 g,containing some TEA) which was used in the next step without furtherpurification.

(viii) Benzyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

The title compound was obtained in 55% yield according to the proceduredescribed in Preparation B(iii) above, using 3-benzyl-7-(tert-butyl)9-oxa-3,7-diazabicyclo[3.3.1]nonane-3,7-dicarboxylate (from step (vii)above) in place of tert-butyl7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.

(ix) Benzyl7-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-cyanophenoxy)-propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

The sub-title compound was obtained in 71% yield according to theprocedure described in Preparation B(ii) above, using benzyl9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (viii)above) and tert-butyl(2S)-2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate (from step (vi)above) in place of tert-butyl9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate and4-[(2S)-oxiranylmethoxy]benzonitrile, respectively.

(x) tert-Butyl(1S)-2-(4-cyanophenoxy)-1-(9-oxa-3,7-diazabicyclo[3.3.1]-non-3-ylmethyl)ethylcarbamate

A solution of benzyl7-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(from step (ix) above; 2.55 g, 4.7 mmol) in 95% ethanol (50 mL) washydrogenated over 5% Pd/C (0.8 g) at 30 kPa. When the quantity ofhydrogen calculated for complete reaction had been consumed, thereaction was stopped. The mixture was filtered through Celite®, and thefiltrate concentrated in vacuo. The resulting residue was purified bychromatography on silica, eluting with CHCl₃:ammoniacal methanol (95:5),to yield the title compound 1.39 g (75%).

Preparation K

4-{[2-Hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]oxy}-benzonitrile

The title compound was prepared according to the method described inpreparation B above, using epichlorohydrin in place of(R)-(−)-epichlorohydrin in step (i).

Preparation L

2,6-Bis(hydroxymethyl)-4-(phenylsulfonyl)morpholine (i)N,N-Bis(2-oxiranylmethyl)benzenesulfonamide

This reaction is very exothermic so care must be taken if the reactionis scaled up. Acetonitrile (400 mL) and (±)-epichlorohydrin (100 mL,118.3 g, 0.78 mol) were added to benzenesulfonamide (50.0 g, 0.32 mol),followed by cesium carbonate (228 g, 0.70 mol). The mixture was heatedat reflux for 15 hours with mechanical stirring. After cooling to roomtemperature water was added (250 mL) and the organic phase separated andconcentrated under reduced pressure. The residual oil waschromatographed over silica (300 g), eluting with dichloromethane (1 L)and then dichloromethane:ethyl acetate (3 L of 19:1), to give thesub-title compound as an oil (39.4 g, 46%).

¹H NMR (400 MHz, CDCl₃): δ 2.55-2.65 (2H, m), 2.79 (2H, t, J 4.4),3.10-3.22 (4H, m), 3.58-3.73 (2H, m), 7.50-7.56 (2H, m), 7.58-7.63 (1H,m), 7.83-7.87 (2H, m).

(ii) 2,6-Bis(hydroxymethyl)-4-(phenylsulfonyl)morpholine

Tetrahydrofuran (40 mL) was added toN,N-bis(2-oxiranylmethyl)benzenesulfonamide (from step (i) (alternativeA) above; 10 g, 37.1 mmol), followed by dilute sulfuric acid (10 mL of 1M), and the mixture stirred for 6 days (reaction is complete within 1day). Solid sodium chloride (3 g) and ethyl acetate (40 mL) were added,and the mixture stirred for 1 hour. The organic phase was separated andwashed with aqueous ammonium chloride (10 mL of 10%). The organic phasewas concentrated under reduced pressure before toluene was added (50mL). The mixture was concentrated again to leave the title compound as acrude oil (10.65 g). This material was employed directly in subsequentreactions without any further purification.

Preparation M

cis-2,6-Bis(hydroxymethyl)-4-(phenylsulfonyl)morpholine (i) Chirallyenriched N,N-bis(2-oxiranylmethyl)benzenesulfonamide

This reaction is very exothermic so care must be taken if the reactionis scaled up. Acetonitrile (100 mL) and (R)-(−)-epichlorohydrin (47 mL,55.6 g, 0.60 mol) were added to benzenesulfonamide (20.0 g, 0.127 mol),followed by cesium carbonate (83 g, 0.255 mol). The mixture was heatedat reflux for 6 hours with mechanical stirring and then was stirredovernight at room temperature. Water was added (100 mL), the organicphase separated and then concentrated under reduced pressure. Theresidual oil was chromatographed over silica, eluting withdichloromethane then dichloromethane:ethyl acetate (19:1), to give thesub-title compound as an oil (14.8 g, 43%).

(ii) cis-2,6-Bis(hydroxymethyl)-4-(phenylsulfonyl)morpholine

Tetrahydrofuran (60 mL) was added to chirally-enrichedN,N-bis(2-oxiranylmethyl)benzenesulfonamide (from step (i) above; 14.8g, 55 mmol), followed by dilute sulfuric acid (15 mL of 1 M), and themixture stirred for 3 days. Solid sodium chloride (11 g) was added andthe mixture stirred for 1 hour. The organic phase was separated andconcentrated under reduced pressure to give crude product (22.4 g). Thematerial was purified by column chromatography over silica, eluting withdichloromethane:ethanol (19:1), to give the title compound (4 g, 25%)and an impure fraction that was a 2:1 mixture of cis- and trans-isomers(8 g, 75%).

The cis-isomer is also ultimately formed as the major product if(S)-(+)-epichlorohydrin is used in step (i) in place of(R)-(−)-epichlorohydrin.

Preparation N

3,3-Dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone (i)N,N-Bis(2-oxiranylmethyl)benzenesulfonamide

The following is an alternative preparation to that described inPreparation L(i) above.

Water (2.5 L, 10 vol.) followed by epichlorohydrin (500 mL, 4 eq.) wereadded to benzenesulfonamide (250 g, 1 eq.). The reactants were heated to40° C. Aqueous sodium hydroxide (130 g in 275 mL of water) was addedsuch that the temperature of the reaction remained between 40° C. and43° C. This took approximately 2 hours. (The rate of sodium hydroxideaddition needs to be slower at the start of the addition than at the endin order to keep within the temperature range stated.) After theaddition of sodium hydroxide was complete, the reaction was stirred at40° C. for 2 hours, then at ambient temperature overnight. The excessepichlorohydrin was removed as a water azeotrope by vacuum distillation(ca. 40 mbar, internal temp 30° C.), until no more epichlorohydrindistilled. Dichloromethane (1 L) was added and the mixture stirredrapidly for 15 minutes. The phases were allowed to separate (this took10 minutes although totally clear phases are obtained after standingovernight). The phases were separated and the dichloromethane solutionused in the subsequent step below.

¹H NMR (400 MHz, CDCl₃): δ 2.55-2.65 (2H, m), 2.79 (2H, t, J 4.4),3.10-3.22 (4H, m), 3.58-3.73 (2H, m), 7.50-7.56 (2H, m), 7.58-7.63 (1H,m), 7.83-7.87 (2H, m).

(ii) 5-Benzyl-3,7-dihydroxy-1-phenylsulfonyl-1,5-diazacyclooctane

IMS (2.5 L, 10 vol) was added to the dichloromethane solution from step(i) above. The solution was distilled until the internal temperaturereached is 70° C. Approximately 1250 mL of solvent was collected. MoreIMS (2.5 L, 10 vol) was added followed by benzylamine (120 mL, 0.7 eq.)in one portion (no exotherm seen), and the reaction was heated at refluxfor 6 hours (no change from 2 hour sampling point). More benzylamine wasadded (15 mL) and the solution was heated for a further 2 hours. The IMSwas distilled off (ca. 3.25 L) and toluene was added (2.5 L). Moresolvent was distilled (ca. 2.4 L) and then further toluene added (1 L).The head temperature was now 110° C. A further 250 mL of solvent wascollected at 110° C. Theoretically, this left the product in ca. 2.4 Lof toluene at 110° C. This solution was used in the next step.

¹H NMR (400 MHz, CDCl₃): δ 7.83-7.80 (4H, m, ArH), 7.63-7.51 (6H, m,ArH), 7.30-7.21 (10H, ArH), 3.89-3.80 (4H, m, CH(a)+CH(b)), 3.73 (2H, s,CH₂Ph(a)), 3.70 (2H, s, CH₂Ph(b)), 3.59 (2H, dd, CHHNSO₂Ar(a)), 3.54(2H, dd, CHHNSO₂Ar(b)), 3.40 (2H, dd, CHHNSO₂Ar(b)), 3.23 (2H, dd,CHHNSO₂Ar(a)), 3.09-2.97 (4H, m, CHHNBn(a)+CHHNBn(b)), 2.83 (2H, dd,CHHNBn(b)), 2.71 (2H, dd, CHHNBn(a))

(Data taken from purified material comprising a 1:1 mixture of trans-(a), and cis-diol (b))

(iii) 3-Benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane

The following is an alternative preparation to that described inPreparation A(ii) above.

The toluene solution from the previous step (ii) above was cooled to 50°C. Anhydrous methanesulfonic acid (0.2 L) was added. This caused atemperature rise from 50° C. to 64° C. After 10 minutes, methanesulfonicacid was added (1 L) and the reaction heated to 110° C. for 5 hours.Toluene was then-distilled from the reaction; 1.23 L was collected.(Note that the internal temperature should not be allowed higher than110° C. at any stage otherwise the yield will be decreased.) Thereaction was then cooled to 50° C. and a vacuum applied to remove therest of the toluene. Heating to 110° C. and 650 mbar allowed a further0.53 L to be removed. (If the toluene can be removed at a lowertemperature and pressure then that is beneficial.) The reaction was thenleft to cool to 30° C. and deionised water (250 mL) was added. Thiscaused the temperature to rise from 30° C. to 45° C. More water (2.15 L)was added over a total time of 30 minutes such that the temperature wasless than 54° C. The solution was cooled to 30° C. and thendichloromethane (2 L) was added. With external cooling and rapidstirring, the reaction mixture was basified by adding aqueous sodiumhydroxide (10 M, 2 L) at a rate that kept the internal temperature below38° C. This took 80 minutes. The stirring was stopped and the phasesseparated in 3 minutes. The layers were partitioned. IMS (2 L) was addedto the dichloromethane solution and distillation started. Solvent (2.44L) was collected until the head temperature reached 70° C.Theoretically, this left the product in 1.56 L of IMS. The solution wasthen allowed to cool to ambient temperature overnight with slowstirring. The solid product that precipitated was filtered and washedwith IMS (0.5 L) to give a fawn-coloured product that, on drying at 50°C., in vacuum, gave 50.8 g (8.9% over 3 steps). 20.0 g of this productwas dissolved in acetonitrile (100 mL) at reflux to give a pale yellowsolution. After cooling to ambient temperature, the crystals that formedwere collected by filtration and washed with acetonitrile (100 mL). Theproduct was dried in vacuo at 40° C. for 1 hour to give 17.5 g (87%) ofsub-title compound.

¹H NMR (400 MHz, CDCl₃): δ 7.18-7.23 (10H, m), 3.86-3.84 (2H, m), 3.67(2H, d), 3.46 (2H, s), 2.91 (2H, d), 2.85 (2H, dd), 2.56 (2H, dd)

(iv) 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane×2 HCl

This is an alternative preparation to that described in PreparationA(iii) above.

Concentrated hydrobromic acid (1.2 L, 3 rel. vol.) was added to solid3-benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane (400 g,see step (iii) above) and the mixture was heated to reflux under anitrogen atmosphere. The solid dissolved in the acid at 95° C. Afterheating the reaction for 8 hours, HPLC analysis showed that the reactionwas complete. The contents were cooled to room temperature. Toluene (1.2L, 3 rel. vol.) was added and the mixture stirred vigorously for 15minutes. Stirring was stopped and the phases were partitioned. Thetoluene phase was discarded along with a small amount of interfacialmaterial. The acidic phase was returned to the original reaction vesseland sodium hydroxide (10 M, 1.4 L, 3.5 rel. vol.) was added in oneportion. The internal temperature rose from 30° C. to 80° C. The pH waschecked to ensure it was >14. Toluene (1.6 L, 4 rel. vol.) was added andthe temperature fell from 80° C. to 60° C. After vigorous stirring for30 minutes, the phases were partitioned. The aqueous layer was discardedalong with a small amount of interfacial material. The toluene phase wasreturned to the original reaction vessel, and 2-propanol (4 L, 10 rel.vol.) was added. The temperature was adjusted to between 40° C. and 45°C. Concentrated hydrochloric acid (200 mL) was added over 45 minutessuch that the temperature remained at between 40° C. and 45° C. A whiteprecipitate formed. The mixture was stirred for 30 minutes and thencooled to 7° C. The product was collected by filtration, washed with2-propanol (0.8 L, 2 rel vol.), dried by suction and then further driedin a vacuum oven at 40° C. Yield=297 g (91%).

¹H NMR (CD₃OD+4 drops D₂O): δ 2.70 (br d, 2H), 3.09 (d, 2H), 3.47 (br s,4H), 3.60 (s, 2H), 4.12 (br s, 2H), 7.30-7.45 (m, 5H).

API MS: m/z=219 [C₁₃H₁₈N₂O+H]⁺.

(v)3,3-Dimethyl-1-[9-oxa-7-(phenylmethyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-2-butanone

Water (500 mL, 5 vol.) followed by 1-chloropinacolone (45.8 mL, 1 eq.)were added to sodium bicarbonate (114.2 g, 4 eq.). A solution of3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane×2 HCl (100.0 g; see step(iv) above) in water (300 mL, 3 vol.) was added slowly, so that theevolution of carbon dioxide was controlled (20 mins.). The reactionmixture was heated at 65 to 70° C. for 4 hours. After cooling to ambienttemperature, dichloromethane (400 mL, 4 vol.) was added and, afterstirring for 15 minutes, the phases were separated. The aqueous phasewas washed with dichloromethane (400 mL, 4 vol.) and the organicextracts combined. The solution was distilled and solvent collected (550mL). Ethanol (1 L) was added and the distillation continued. Furthersolvent was collected (600 mL). Ethanol (1 L) was added and thedistillation continued. Further solvent was collected (500 mL) (the headtemperature was now 77° C.). This solution (theoretically containing1150 mL of ethanol) was used directly in the next step.

¹H NMR (400 MHz, CDCl₃): δ 1.21 (9H, s), 2.01-2.59 (2H, m), 2.61-2.65(2H, m), 2.87-2.98 (4H, m), 3.30 (2H, s), 3.52 (2H, s), 3.87 (2H, br s),7.26 (2H, d, J 7.6), 7.33 (1H, dd, J 7.6, 7.6), 7.47 (2H, d, J 7.6).

(vi) 3,3-Dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone

Palladium on charcoal (44 g, 0.4 wt. eq. of 61% wet catalyst, JohnsonMatthey Type 440L) was added to the ethanol solution from the previousstep (v) above. The mixture was hydrogenated at 4 bar. The reaction wasconsidered complete after 5 hours. The catalyst was removed byfiltration and washed with ethanol (200 mL). The combined ethanolfiltrates were used in Example 3 below. Solution assay gave 61.8 g oftitle product in ethanol (theoretically 1.35 L; measured 1.65 L). Aportion of the product was isolated and purified. Analysis was performedon the purified product.

¹H NMR (300 MHz, CDCl₃): δ 1.17 (9H, s), 2.69 (2H, dt, J 11.4, 2.4),2.93 (2H, d, J 10.8), 3.02 (2H, d, J 13.8), 3.26 (2H, s), 3.32 (2H, dt,J 14.1), 3.61 (2H, br s).

Preparation O

2-(4-Acetyl-1-piperazinyl)ethyl 1H-imidazole-1-carboxylate (i)1-[4-(2-Hydroxyethyl)-1-piperazinyl]-1-ethanone

A solution of 2-(1-piperazinyl)-1-ethanol (6.5 g 0.05 mol) in DCM (5 mL)was treated with acetic acid anhydride (5.1 g, 0.05 mol), addeddropwise. During addition, the reaction temperature rose from 22 to 60°C. The reaction mixture was evaporated several times with toluene toyield 5.6 g (65%) of the sub-title compound.

(ii) 2-(4-Acetyl-1-piperazinyl)ethyl 1H-imidazole-1-carboxylate

A solution of 1,1′-carbonyldiimidazole (5 g, 31 mmol) in DCM (200 mL)was treated with a solution of1-[4-(2-hydroxyethyl)-1-piperazinyl]-1-ethanone (from step (i) above; 5g, 29 mmol) in DCM (50 mL). The reaction mixture was stirred at rtovernight before water was added. The layers were separated, and theorganic layer was washed with water, dried and concentrated in vacuo toyield 7.4 g (96%) of the title compound.

Preparation P

1-[4-(3-Bromopropyl)-1-piperazinyl]-1-ethanone

A mixture of 1-(1-piperazinyl)-1-ethanone (6.7 g, 0.052 mol),dibromopropane (330 mL, excess) and K₂CO₃ (10.2 g, 0.079 mol) wasstirred at rt for 4 h. The mixture was washed with 4×100 mL of water,and the organic phase (diluted with DCM) was acidified with aqueoushydrobromic acid (7 mL of 62% HBr dissolved in 150 mL of water). Theorganic layer was separated and washed with water (2×50 mL). Thecombined water layers were extracted with ether, neutralised (to pH 7)with 13 mL of 10 M NaOH, and then extracted with DCM. The combinedorganic layers were dried and concentrated in vacuo to give 4.1 g (32%)of the title compound.

Preparation Q

3-(Ethylsulfonyl)propyl 4-methylbenzenesulfonate (i)3-(Ethylsulfonyl)-1-propanol

A solution of 3-(ethylthio)-1-propanol (13 g, 0.11 mol) in acetic acid(40 mL) was treated with H₂O₂ (30% in water, 12.2 g, 0.11 mol), addeddropwise. The mixture was stirred for 2 h at rt, before beingconcentrated in vacuo. NMR analysis showed that the resulting residueconsisted of 40% of the desired product and 60% of the correspondingO-acetate. The acetate was hydrolysed by dissolving the reaction mixturein 200 mL of methanol and adding 3 g of NaOH (dissolved in a smallamount of water). This mixture was stirred overnight at rt, thenconcentrated in vacuo. The resulting crude product was dissolved in DCM,and insoluble material was filtered off. The DCM was removed byevaporation to give 13.4 g (88%) of the sub-title compound.

(ii) 3-(Ethylsulfonyl)propyl 4-methylbenzenesulfonate

A mixture of 3-(ethylsulfonyl)-1-propanol (from step (i) above; 13.4 g,88 mmol) and p-toluenesulfonyl chloride (16.8 g, 88 mmol) in DCM (150mL) was treated with TEA (13.4 g, 132 mmol), added dropwise. Theresulting mixture was stirred at rt for 3 h before being washed withaqueous ammonium chloride solution. The organic layer was thenseparated, dried and concentrated in vacuo. The product was crystallisedfrom ether containing a small amount of DCM to yield 17.9 g (66%) of thetitle compound.

Preparation R

tert-Butyl 2-bromoethylcarbamate

Sodium bicarbonate (6.15 g, 0.073 mol) and di-t-butyl dicarbonate (11.18g, 0.051 mol) were dissolved in a mixture of H₂O (50 mL) anddichloromethane (150 mL), then cooled to 0° C. 2-Bromoethylaminehydrobromide (10.0 g, 0.049 mol) was added slowly as a solid, and thereaction was stirred overnight at 25° C. The dichloromethane layer wasseparated, washed with H₂O (200 mL) and washed with a solution ofpotassium hydrogensulfate (150 mL, pH=3.5). The organic layer was dried(Na₂SO₄) and concentrated in vacuo. The crude oil was chromatographed onsilica gel, eluting with dichloromethane to afford 7.87 g (72%) of thesub-title compound as a clear, colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 4.98 (bs, 1H), 3.45-3.57 (m, 4H), 1.47 (s, 9H)

API-MS: (M+1−C₅H₈O₂) 126 m/z

Preparation S

2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate

A cooled (0° C.) mixture of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-ethanol(0.48 g, 3.4 mmol) and triethylamine (0.47 mL, 3.4 mmol) in MeCN (5 mL)was treated with 4-methylbenzenesulfonyl chloride (0.72 g, 3.8 mmol),after which the mixture was kept cool in a refrigerator for 2 days. Themixture was then concentrated in vacuo to give a residue which waspurified by chromatography on silica gel, eluting with ethyl acetatehexane (1:1), to give 0.46 g (46%) of the title compound.

Preparation T

4-(2-Bromoethoxy)phenyl tert-butyl ether

A solution of KOH (0.224 g, 4 mmol) in MeOH (3 mL) was added, over thecourse of 30 min, to a warmed (70° C.) mixture of 1,2-dibromoethane (3g, 0.016 mol) and 4-(tert-butoxy)phenol (0.66 g, 0.004 mol). The mixturewas stirred at 70° C. for 15 h before water and CHCl₃ were added. Thelayers were separated, the organic layer washed with 10% aqueous NaOHand then dried (Na₂SO₄) and concentrated in vacuo to give 0.32 g (28%)of the sub-title compound.

Preparation U

3-Benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane viaChirally-Enriched5-Benzyl-3,7-dihydroxy-1-phenylsufonyl-1,5-diazacyclooctane (i)Chirally-Enriched N,N-Bis(2-oxiranylmethyl)benzenesulfonamide

The following is an alternative procedure to that described inPreparation M(i) above:

Water (100 mL, 10 vol) followed by (S)-epichlorohydrin (20 mL, 4 eq.)were added to benzenesulfonamide (10 g, 1 eq.). The reactants wereheated to 40° C. Aqueous sodium hydroxide (10 M, 13 mL) was added overone hour, such that the temperature of the reaction mixture remainedbetween 37° C. and 43° C. The reaction was then stirred at 40° C. for 2hours and at ambient temperature overnight. The excess epichlorohydrinwas removed as a water azeotrope by vacuum distillation (ca. 30 mbar,internal temp 30° C.) until no more epichlorohydrin distilled.Dichloromethane (200 mL) was added and the mixture was stirred rapidlyfor 15 minutes. The mixture was then separated and the dichloromethanelayer was concentrated in vacuo to give a colourless oil, which was usedin the next step without further purification.

¹H NMR (400 MHz, CDCl₃): δ 7.51-7.87 (m, 5H), 3.65-3.54 (4H, m),3.24-3.08 (4H, m), 2.82-2.77 (1H, m), 2.61-2.55 (1H, m)

(ii) Chirally-Enriched5-Benzyl-3,7-dihydroxy-1-phenylsufonyl-1,5-diazacyclooctane

The crude product from step (i) above was dissolved in ethanol (200 mL)and treated at room temperature with benzylamine (6.9 mL, 1 equiv.) inone portion (no exotherm was observed). The mixture was heated to refluxfor 4 hours, and was then stirred at ambient temperature overnight. Thesolvent was removed in vacuo to give a viscous, colourless oil which wasused in the subsequent step without further purification.

¹H NMR (400 MHz, CDCl₃): δ 7.83-7.80 (2H, m, ArH), 7.63-7.51 (3H, m,ArH), 7.30-7.21 (5H, ArH), 3.89-3.80 (2H, m, CH), 3.73 (2H, s, CH₂Ph),3.59 (2H, dd, CHHNSO₂Ar), 3.23 (2H, dd, CHHNSO₂Ar), 3.09-2.97 (2H, m,CHHNBn), 2.71 (2H, dd, CHHNBn).

(iii) 3-Benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane

The crude product from step (ii) above was dissolved in warm toluene(150 mL) and treated with anhydrous methanesulfonic acid (50 mL).Toluene (105 mL) was removed from the mixture by distillation at reducedpressure (28 mbar). The remaining mixture was then heated to 110° C. for6.5 h. The mixture was allowed to cool to 30° C. and the remainingtoluene removed by distillation under reduced pressure (25 mbar). Themixture was cooled in an ice/water bath to 40° C. and then treated withwater (100 mL), which caused the internal temperature to rise to 70° C.After cooling to 20° C. dichloromethane (80 mL) was added. The mixturewas basified by the portionwise addition of aqueous sodium hydroxidesolution (10 M, 80 mL), such that the internal temperature remainedbelow 30° C. This took 20 minutes. The dicholoromethane layer wasseparated and evaporated nearly to dryness in vacuo. Methanol (50 mL)was added and the solvent was again removed in vacuo. The resultingsolid was suspended in MeOH (50 mL) and filtered. The filter cake waswashed with methanol (20 mL) and the resulting solid dried by airsuction to give the title compound as a white crystalline solid (3.46 g,15% over 3 steps).

The following intermediates were either commercially available or wereprepared according to published methods:

-   ethyl isocyanate;-   1-butanesulfonyl chloride;-   1-chloropinacolone;-   3,4-dimethoxyphenethyl methanesulfonate;-   1-(chloromethyl)cyclopropane;-   2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-ethanone;-   5-(2-chloroethyl)-4-7-methyl-1,3-thiazole;-   2-chloro-N-isopropylacetamide;-   1-bromo-2-(2-methoxyethoxy)ethane;-   4-fluorobenzyl bromide;-   2-bromo-4′-methoxyacetophenone;-   2-chloro-1-(4-fluorophenyl)-1-ethanone;-   2-(bromomethyl)tetrahydro-2H-pyran;-   1-bromo-3,3-dimethylbutane;-   chloroacetone;-   N,N-diethylchloroacetamide;-   4-chloro-1-(4-fluorophenyl)-1-butanone;-   4-(bromomethyl)benzonitrile;-   1-(bromomethyl)-2,4-difluorobenzene;-   4-(difluoromethoxy)benzyl bromide;-   1-(2-bromoethyl)pyrrole;-   1-(4-bromophenyl)-3-chloro-1-propanone;-   2-bromo-1,1-difluoroethane;-   1-(2-bromoethoxy)benzene;-   2-(chloromethyl)imidazo[1,2-a]pyridine;-   4-(2-chloroethyl)-1H-imidazole;-   2-bromo-1-[4-(1-pyrrolidinyl)phenyl]-1-ethanone;-   2-chloro-1-(4-hydroxyphenyl)-1-ethanone;-   2-bromo-1-(4-methylphenyl)-1-ethanone;-   2-bromo-1-(4-methoxyphenyl)-1-ethanone;-   2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-ethanone;-   6-(2-chloroacetyl)-2H-1,4-benzoxazin-3 (4H)-one;-   N-(tert-butyl)-N′-(2-chloroethyl)urea;-   1-(chloromethyl)benzene; and-   tert-butyl 2-(bromomethyl)—1-pyrrolidinecarboxylate.    Synthesis of Compounds of Formula I

Example 14-{2-[7-(3,3-Dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzonitrile(i) tert-Butyl7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate

A mixture of tert-butyl9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride(Preparation A; 0.26 g, 1.0 mmol) and K₂CO₃ (1.45 g, 10.5 mmol) in MeCN(8 mL) was treated with 1-chloropinacolone (0.216 g, 1.6 mmol), and themixture stirred at 40° C. overnight. The following morning, thetemperature was raised to 50° C. for 4 h before the solids were filteredoff from the mixture and the filtrate concentrated in vacuo. The crudeproduct was dissolved in DCM and the solution was added to anion-exchange solid phase extraction plug (10 g CBA (carboxylic acid onsilica support)). After 1 h, the plug was washed with DCM (15 mL), afterwhich the product was finally eluted with dichloromethane:MeOH:TEA(90:5:5). The solvents were evaporated to give 0.276 g (85.5%) of thesub-title compound.

(ii) 3,3-Dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone

The following is an alternative preparation to that described inPreparation N(v) above:

A solution of tert-butyl7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(from step (i) above; 0.265 g, 0.812 mmol) in ethyl acetate (10 mL) wastreated, at 0° C., with ethyl acetate saturated with gaseoushydrochloric acid. The mixture was stirred at 0° C. for 5 h, and thenevaporated. Acetonitrile (15 mL) and K₂CO₃ (1 g, 7.2 mmol) were added,and the mixture was stirred overnight before being filtered andevaporated to yield 0.159 g (86%) of the sub-title compound.

(iii) 4-Cyanophenethyl methanesulfonate

Methanesulfonyl chloride (18.6 g, 164 mmol) was added to a stirredsolution of 4-(2-hydroxyethyl)benzonitrile (20 g, 136 mmol) andtriethylamine (20.6 g, 204 mmol) in DCM (200 mL) at 0° C. The reactionmixture was stirred at rt until the reaction was complete (as indicatedby tlc). Water (200 mL) was added and the organic layer was separated,dried and concentrated to give the sub-title compound in a quantitativeyield.

(iv)4-{2-[7-(3,3-Dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}benzonitrile

A mixture of3,3-dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone (fromstep (ii) above; 56 mg, 0.25 mmol), TEA (0.35 mL, 2.5 mmol) and MeCN (2mL) was treated with 4-cyanophenethyl methanesulfonate (see step (iii)above; 84 mg, 0.37 mmol). The resulting mixture was stirred at 50° C.for 24 h. The solvents were removed by evaporation, the crude productwas dissolved in DCM and then the solution was added to an ion-exchangesolid-phase extraction plug (2 g, CBA (carboxylic acid on silicasupport)). After 1 h, the plug was washed with DCM (15 mL), after whichthe product was finally eluted with DCM:MeOH:TEA (90:5:5), to give 84 mg(95%) of the title compound.

MS (ES): m/z=355.9 (M)⁺.

Example 27-[4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-N-ethyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide

A solution of ethyl isocyanate (18.8 mg, 0.25 mmol) in MeCN (2 mL) wasadded, together with K₂CO₃ (34.5 mg, 0.25 mmol), to a solution of4-[1-(3,4-dimethoxyphenoxy)-4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-butyl]benzonitrile(Preparation H, 109.4 mg, 0.25 mmol) in chloroform (0.5 mL). Thereaction mixture was stirred at rt for 4 days before being added to asolid phase extraction plug (SiO₂, 0.5 g). The plug was washed withCHCl₃:MeCN (2.5 mL of 80:20), and the product was finally eluted withCHCl₃:MeOH (3×2.5 mL of 95:5) to give the title compound.

MS (ES): m/z=508.3 (M)⁺

Example 34-({3-[7-(3,3-Dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile

Alternative A

A mixture of4-{[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}-benzonitrile(Preparation C, 5.73 g 0.02 mol), K₂CO₃ (11.05 g, 0.08 mol) in MeCN (300mL) was treated with 1-chloropinacolone (4.44 g, 0.032 mol). The mixturewas stirred at 50° C. overnight before DCM was added and the mixturefiltered. The filter cake was then washed with a mixture of DCM and MeCNbefore the solvent was evaporated from the filtrate. The resultingresidue was purified by chromatography on silica, eluting with agradient of ethyl acetate methanol:ammoniacal methanol (95:5:0 to95:0:5), to give the title compound (5.8 g, 73.9%).

Alternative B—Preparation via Benzenesulfonic Acid Salt

(i)4-({3-[7-(3,3-Dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile,benzenesulfonic acid salt monohydrate

Potassium carbonate (56.6 g, 1.5 equiv) and3-(4-cyanoanilino)propyl-4-methylbenzenesulfonate (see Preparation C(ii)above, 90.3 g, 1 equiv) were added to the ethanol solution of3,3-dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone (seePreparation N, 61.8 g from assay in 1.65 L). The reaction was heated at80° C. for 4 hours. An assay showed some reactant remained (8.3 g), somore 3-(4-cyanoanilino)propyl-4-methylbenzenesulfonate (12.2 g) wasadded, and the resultant was heated at 80° C. for 4 hours. Solvent (1.35L) was distilled, then isopropyl acetate (2.5 L) added. Solvent (2.51 L)was removed. Isopropyl acetate (2.5 L) was added. Solvent (0.725 L) wasremoved. The internal temperature was now at 88° C. Solvent (0.825 L)was removed, leaving the product as an isopropylacetate solution(theoretically in 2.04 L). After cooling to 34° C., water (0.5 L) wasadded. There was a black suspension, possibly of Pd, in the mixture. ThepH of the aqueous phase was 11. Sodium hydroxide (1 M, 0.31 L) wasadded, so that the temperature was less than 25° C., and the mixture wasstirred vigourously for 5 minutes. The pH of the aqueous phase was 12.The phases were separated and the aqueous phase discarded. More water(0.5 L) was added, and the phases were separated. The aqueous phase wasdiscarded. The remaining ester solution was filtered to remove suspendedparticles, and the filtrate was then made up to exactly 2 L. Thesolution was then split into 2×1 L portions.

(In order to avoid producing sub-title product comprising a highpalladium content, the following treatment may be performed: Deloxan®resin (12.5 g, 25 wt %) was added to the solution of the free base (1L), and the mixture heated at reflux with vigorous stirring for 5 hours.The solution was then cooled to room temperature, and was stirred for 2days. The resin was removed by filtration.)

An assay was performed to calculate the required amount ofbenzenesulfonic acid, to make the benzenesulfonate salt.

A solution of benzenesulfonic acid (20.04 g, 1 eq., assuming acid waspure monohydrate) in isopropyl acetate (200 mL) was added over 5 minutes(better to add slower if possible) with vigorous stirring to thesolution of the free base (1 L) and a pale yellow precipitate formed.The temperature rose from 18° C. to 22° C. After 10 minutes, the mixturewas cooled to 10° C. and the product collected by filtration. Theproduct was washed with isopropyl acetate (250 mL), sucked dry on thefilter then dried under vacuum at 40° C. for 2 days to give 59.0 g (61%from 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane×2HCl).

(The crude benzenesulfonate salt was alternatively prepared by theaddition of a 70% (w/w) aqueous solution of benzenesulfonic acid to anethanolic solution of the free base.)

The crude sub-title product is isolated as a monohydrate.

Ethanol (500 mL) and water (250 mL) were added to crude sub-titlecompound (50.0 g). The solution was heated to 75° C. Material was alldissolved at 55° C. The solution was held at 75° C. for 5 minutes, thencooled to 5° C. over 1 hour. Precipitation started at 18° C. The cold issolution was filtered and the filtrate washed with ethanol:water (2:1;150 mL), sucked dry on the filter, and then dried in vacuo at 40° C. togive pure sub-title product (41.2 g, 82%).

(This recrystallisation may be carried out with greater volumes ofsolvent if necessary to fit the reaction vessels e.g.

EtOH:water 2:1, 45 vol. (gave 62% recovery)

EtOH:water 6:1, 35 vol. (gave 70% recovery).)

The sub-title product was isolated as the monohydrate following therescrystallisation (as determined by single crystal X-ray diffraction).

(ii)4-({3-[7-(3,3-Dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile

Crude benzenesulfonate salt (50.0 g, 1.0 equiv, from step (i) above) wasadded to aqueous sodium hydroxide (1M, 500 mL) washing in withdichloromethane (1.0 L, 20 vol). The combined mixture was stirred for 15minutes. The layers were then separated and a small amount ofinterfacial material was left with the upper aqueous layer. Ethanol (500mL, 10 vol) was added to the dichloromethane solution and then solventwas removed by distillation (1.25 L). The still head temperature was nowat 78° C. The solution was allowed to cool to below reflux and ethanol(250 mL, 5 vol.) was added. Solvent was removed (250 mL). This warmsolution was diluted with ethanol to 890 mL, 17.8 vol. (25 vol. assuming100% conversion to free base). After heating to reflux the solution wascooled slowly. At 5° C. a seed of title compound was added.Crystallisation began and the mixture was stirred at 5° C. for 30minutes. The product was collected by filtration and washed with ethanol(2×50 mL, 2×1 vol.). The product was then dried in a vacuum oven at 40°C. for 60 hours to give an off-white powder (26.3 g; 74%).

¹H NMR (400 MHz, CDCl₃): δ 7.86-7.82 (2H, m), 7.39-7.32 (3H, m),7.30-7.26 (2H, m), 6.47 (2H, m), 4.11-4.07 (4H, m), 3.70 (2H, s),3.36-3.33 (4H, m), 3.26 (2H, t), 3.12 (2H, d), 2.90 (2H, d), 2.28-2.21(2H, m), 1.06 (9H, s).

¹³C NMR (CDCl₃): δ 24.07, 26.38, 41.52, 43.52, 56.17, 56.47, 63.17,68.46, 96.61, 111.64, 121.03, 133.43.

MS (ES): m/z=385.1 (M+H)⁺

Example 44-{3-[7-(4-Fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile

A solution of 4-fluorobenzyl bromide (14.17 mg, 0.075 mmol) in DCM (0.5mL) of was added, together with TEA (20 mg, 0.2 mmol) to a solution of4-{[2-hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-propyl]oxy}benzonitrile(Preparation K; 15.2 mg, 0.05 mmol) in MeCN (0.5 mL). The mixture wasstirred at 50° C. for 4 days before being concentrated in vacuo. Theresulting residue was dissolved in CHCl₃ and added to a solid-phaseextraction plug (CBA, 0.4 g). The plug was washed with CHCl₃ (4×0.3 mL),and the product was finally eluted with CHCl₃:MeOH:TEA (5×0.3 mL of8:1:1) to give the title compound.

MS (ES): m/z=412.5 (M+H)⁺.

Example 54-(2-{7-[2-(4-Methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethoxy)benzonitrile

A mixture of4-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethoxy]benzonitrile(Preparation D; 68.3 mg, 0.25 mmol), 2-bromo-4′-methoxyacetophenone(68.7 mg, 0.3 mmol) and TEA (37.94 mg, 0.37 mmol) in DMF (2.5 mL) wasstirred at rt for 2 days, and then (as reaction was found to beincomplete) at 50° C. for 24 h. The solvent was evaporated and theresidue dissolved in a mixture of MeCN (2.5 mL) and H₂O (0.13 mL).Potassium carbonate (100 mg, 0.72 mmol) was added, and the mixture wasstirred overnight at rt. The mixture was then filtered and the filtrateconcentrated in vacuo. The resulting crude product was dissolved in DCM(2 mL), which solution was added to an ion-exchange solid-phaseextraction plug (CBA, 2 g). After 80 min, the product was eluted withDCM:MeCN (4:1) and then with DCM:MeOH:TEA (8:1:1), to give an impurematerial. This material was purified on a silica plug, eluting withCHCl₃ (2 mL), CHCl₃:CH₃CN (3×2.5 mL of 4:1), and then with CHCl₃:MeOH(10:1), to give 71.5 mg (67.9%) of the title compound.

MS (ES): m/z=422.4 (M+H)⁺.

¹³C NMR (CDCl₃): δ 55.47, 55.89, 56.27, 57.17, 66.57, 66.81, 67.41,102.99, 113.57, 115.73, 119.29, 131.56, 134.32, 162.09, 163.21, 196.25.

Example 64-[((2S)-2-Amino-3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)oxy]benzonitrile

A mixture of tert-butyl(1S)-2-(4-cyanophenoxy)-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)ethylcarbamate(Preparation J; 100.62 mg, 0.25 mmol), 1-(2-bromoethyl)pyrrole (52.21mg, 0.30 mmol) and TEA (37.9 mg, 0.375 mmol) in DMF (2.5 mL) was stirredat rt for 2 days and then at 50° C. for 1 day. The solvent wasevaporated and the resulting residue dissolved in ethyl acetate (0.5mL). Ethyl acetate saturated with gaseous hydrochloric acid (2 mL) wasadded, and the reaction mixture stirred for 1.5 h at rt. The solvent wasevaporated and the resulting residue dissolved in a mixture of MeCN (2.5mL) and H₂O (0.13 mL). Potassium carbonate (100 mg, 0.72 mmol) wasadded, and the mixture stirred overnight at rt. The mixture was filteredand the filtrate concentrated in vacuo. The resulting crude product wasdissolved in DCM (2 mL), which solution was added to a ion-exchangesolid-phase extraction plug (CBA, 2 g). After 80 min, the product waseluted with DCM:MeCN (4×2 mL of 4:1), followed by DCM:MeOH:TEA (8:1:1),to give 89.7 mg (90.7%) of the title compound.

MS (ES): m/z=396.0 (M)⁺

Example 7 tert-Butyl2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate

To a solution of tert-butyl 2-bromoethylcarbamate (4.21 g, 0.019 mol;see Preparation R above) in DMF (65 mL) was added4-{[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}benzonitrile(see Preparation C above, 4.48 g, 0.016 mol) and triethylamine (3.27 mL,0.024 mol). The mixture was stirred overnight at 35° C. and thenconcentrated in vacuo. The residue was dissolved in dichloromethane (80mL) and washed with saturated sodium chloride. The aqueous layer wasextracted with dichloromethane (1×150 mL). The combined organic extractswere dried (Na₂SO₄) and concentrated in vacuo. The crude red-brown oilwas chromatographed (×2) on silica gel eluting withchloroform:methanol:conc. NH₄OH (9:1:0.02) to afford 3.75 g (56%) of thetitle compound.

¹H NMR (300 MHz, CD₃OD) δ 7.37-7.40 (d, J=8.8 Hz, 2H), 6.64-6.67 (d,J=8.8 Hz, 2H), 3.94 (bs, 2H), 3.21-3.31 (m, 4H), 3.01 (bs, 4H),2.47-2.59 (m, 8H), 1.90 (bs, 2H), 1.39 (s, 9H)

¹³C NMR (75 MHz, CD₃OD) δ 158.5, 134.7, 121.9, 113.2, 97.7, 80.3, 69.2,58.8, 58.1, 57.5, 57.3, 41.9, 38.3, 28.9, 26.2.

API-MS: (M+1)=430 m/z

Example 8 tert-Butyl2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate

Triethylamine (2.2 mL, 0.016 mol) and tert-butyl 2-bromoethylcarbamate(see Preparation R above, 2.83 g, 0.013 mol) were added to a solution of4-[4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (seePreparation G above, 3.0 g, 0.011 mol) in DMF (50 mL). The mixture wasstirred for 24 h at 54° C., cooled to 25° C., and concentrated in vacuo.The residue was dissolved in chloroform and washed with saturated sodiumchloride. The aqueous layer was separated and extracted with chloroform(2×150 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. The resulting material was chromatographed onsilica gel, eluting first with chloroform:acetonitrile:conc. ammoniumhydroxide (9:1:0.02) until the higher R_(f) impurities were removed.Then the eluent was switched to chloroform:methanol:conc. ammoniumhydroxide (9:1:0.02). This afforded 2.76 g (61%) of the title compound.

¹H NMR (300 MHz, CD₃OD) δ 7.62-7.64 (d, J=8.1 Hz, 2H), 7.38-7.40 (d,J=8.1 Hz, 2H), 3.84 (s, 2H), 3.14-3.18 (t, J=6.0 Hz, 2H), 2.83-2.93 (m,4H), 2.72-2.77 (t, J=6.9 Hz, 2H), 2.30-2.50 (m, 8H), 1.64-1.68 (m, 4H),1.43 (s, 9H)

¹³C NMR (75 MHz, CD₃OD) δ 158.4, 149.6, 133.4, 130.7, 120.1, 110.7,79.9, 69.8, 61.1, 58.7, 57.7, 57.1, 38.0, 36.9, 30.2, 29.0, 26.7

Example 9 tert-Butyl2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate

Triethylamine (8.56 mL, 0.061 mol) and tert-butyl 2-bromoethylcarbamate(see Preparation R above, 11.0 g, 0.049 mol) were added to a solution of4-{[(2S)-2-hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-propyl]oxy}benzonitrile(see preparation B above, 12.41 g, 0.038 mol) in DMF (100 mL). Themixture was stirred for 20 h at 40° C., then concentrated in vacuo. Theresidue was dissolved in chloroform (100 mL), and washed with saturatedsodium chloride. The aqueous layer was separated and extracted withchloroform (2×150 mL). The combined organic layers were dried (Na₂SO₄)and concentrated in vacuo. The crude brown oil was chromatographed (×2)on silica gel, eluting first with chloroform:methanol (9:1), then withchloroform:methanol:conc. ammonium hydroxide (9:1:0.05) to afford 4.13 g(24%) of the title compound.

¹H NMR (300 MHz, CD₃OD) δ 7.62-7.69 (d, J=8.0 Hz, 2H), 7.09-7.14 (d,J=8.0 Hz, 2H), 4.00-4.17 (m, 3H), 3.87 (s, 2H), 3.18-3.24 (m, 2H),2.88-3.03 (m, 4H), 2.65-2.70 (m, 2H), 2.47-2.55 (m, 4H), 2.31-2.39 (m,2H), 1.41 (s, 9H)

³C NMR (75 MHz, CD₃OD) δ 163.9, 158.3, 135.3, 120.2, 116.7, 104.9, 80.0,72.1, 70.1, 69.9, 67.0, 60.6, 60.2, 58.4, 57.8, 55.7, 38.31, 28.99.

API-MS: (M+1)=447 m/z

Example 104-(2-{7-[4-(4-Pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethoxy)benzonitrile(i) 4-(4-Chlorobutyl)pyridine

4-Methylpyridine (8.4 g, 90 mmol) and THF (40 mL) were mixed in dryglassware, flushed with nitrogen and cooled to −60° C. n-BuLi (1.6 Msolution, 61.9 mL, 99 mmol) was added dropwise over 1.5 h. Thetemperature was not allowed to exceed −50° C. The mixture was thenallowed to reach rt, THF (20 mL) was added and the mixture was thenstirred at 45° C. for 2 h. Additional THF (20 mL) was added. Thismixture was cooled to 0° C. and added dropwise through a cooled droppingfunnel to a 65° C. solution of 3-bromo-1-chloropropane (14.9 g, 94.5mmol) in THF (15 mL). The reaction mixture was slowly allowed to reach0° C. overnight. Water (90 mL) was added, and the mixture was stirredfor 10 min. The organic layer was separated and dried (Na₂SO₄) to givethe sub-title compound in 97.6% yield.

(ii)4-(2-{7-[4-(4-Pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethoxy)benzonitrile

4-[2-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethoxy]benzonitrile (0.80 g,2.92 mmol, see preparation D above) was dissolved in MeCN (30 mL) andmixed with 4-(4-chlorobutyl)pyridine (0.74 g, 4.39 mmol, from step (i)above) and K₂CO₃ (1.62 g, 11.71 mmol). 1 drop of Br₂ was added and themixture was refluxed for 24 h. The mixture was filtered and evaporated.Purification by chromatography on silica, eluting with DCM:4% MeOH(satd. with ammonia), gave 0.68 g (57.2%) of the title compound.

¹³C NMR (CDCl₃) δ 25.78, 27.82, 34.92, 56.28, 56.50, 57.63, 58.99,66.57, 68.11, 103.94, 115.20, 119.07, 123.75, 133.88, 149.57, 151.35,161.91

Example 11 tert-Butyl2-{7-[4-(4-pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate(i) tert-Butyl7-[4-(4-pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate

tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.35 g,5.9 mmol, see Preparation A and Preparation C(iii) above) was mixed with4-(4-chlorobutyl)pyridine (1.35 g, 7.37 mmol, see Example 10(i) above),Br₂ (0.094 g, 0.59 mmol) and K₂CO₃ (3.26 g, 23.6 mmol). The mixture wasrefluxed under argon for 3 days. The reaction mixture was filtered,evaporated and purified by chromatography (DCM, 2-5% MeOH) giving 0.97 g(44%) of the sub-title compound.

¹³C NMR (CDCl₃) δ 25.83, 27.78, 28.48, 35.09, 45.80, 47.16, 56.57,57.42, 58.99, 67.47, 67.72, 79.00, 123.88, 149.60, 151.26, 154.49

(ii) 3-[4-(4-Pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane

tert-Butyl7-[4-(4-pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(0.9 g, 2.5 mmol, from step (i) above) was dissolved in ethylacetate,and then treated with ethylacetate saturated with HCl at 0° C. Themixture was stirred for 1 h at 0° C., and then at rt overnight. Thesolvent was evaporated. CH₃CN (100 mL) and water (2 mL) were addedtogether with K₂CO₃ (3.22 g). The mixture was stirred overnight.Filtration and evaporation gave the sub-title compound in 94% yield.

(iii) tert-Butyl2-{7-[4-(4-pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate

3-[4-(4-Pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane (0.25 g,0.96 mmol, from step (ii) above), tert-butyl 2-bromoethylcarbamate (0.26g, 0.98 mmol, see Preparation R above) and K₂CO₃ (0.4 g, 2.9 mmol) weremixed in CH₃CN (10 mL) and stirred at 50° C. overnight. The reactionmixture was filtered, evaporated and purified by chromatography onsilica (DCM:6% MeOH (satd. with NH₃)). Additional purification byextraction with ether:KHSO₄, basification of the organic phase andextraction with DCM gave the title compound in 51% yield.

³C NMR (CD₃OD) δ 26.65, 28.86, 29.38, 36.02, 38.00, 56.93, 57.58, 58.47,60.93, 69.85, 79.93, 125.65, 149.85, 154.43, 158.40

Example 12

The following compounds were prepared, from appropriate intermediates(such as those described hereinbefore), according to or by analogy withmethods described herein and/or by standard solid or solution phasecombinatorial chemistry techniques (mass spectra of the compounds, whererecorded, are in brackets):

-   4-{3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile    (m/z=402.5);-   4-{3-[7-(3,4-dimethoxyphenethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile    (m/z=467.2);-   4-{2-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethoxy}benzonitrile    (m/z=371.2);-   4-({3-[7-(butylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile    (m/z=406.2);-   4-({3-[7-(3,4-dimethoxyphenethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile    (m/z=450.3);-   4-[4-[7-(butylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile    (m/z=557.3);-   4-{1-(3,4-dimethoxyphenoxy)-4-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]butyl}benzonitrile    (m/z=535.3);-   4-[4-[7-(3,4-dimethoxyphenethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-1-(3,4-dimethoxyphenoxy)butyl]benzonitrile    (m/z=601.3);-   2-(4-acetyl-1-piperazinyl)ethyl    7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate    (m/z=501.3);-   7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-ethyl-9-oxa-3,7-diazabicyclo-[3.3.1]nonane-3-carboxamide    (m/z=374.2);-   4-{3-[7-(butylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile    (m/z=423.4);-   2-(4-acetyl-1-piperazinyl)ethyl    7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate    (m/z=471.2);-   7-[2-(4-cyanophenoxy)ethyl]-N-ethyl-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxamide    (m/z=344.2);-   4-{2-[7-(butylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}-benzonitrile    (m/z=393.2);-   4-{2-[7-(3,4-dimethoxyphenethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}benzonitrile    (m/z=437.2);-   2-(4-acetyl-1-piperazinyl)ethyl    7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate    (m/z=484.3);-   7-[3-(4-cyanoanilino)propyl]-N-ethyl-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxamide    (m/z=357.2);-   2-(4-acetyl-1-piperazinyl)ethyl    7-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate    (m/z=635.3);-   4-{3-[7-(cyclopropylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile    (m/z=358.5);-   4-(3-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-2-hydroxypropoxy)benzonitrile    (m/z=480.5);-   4-(3-{7-[3-(4-acetyl-1-piperazinyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}-2-hydroxypropoxy)benzonitrile    (m/z=472.5);-   2-{7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}-N-isopropylacetamide    (m/z=403.5);-   4-(3-{7-[3-(ethylsulfonyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-2-hydroxypropoxy)benzonitrile    (m/z=438.5);-   4-(2-hydroxy-3-{7-[2-(2-methoxyethoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propoxy)benzonitrile    (m/z=406.5);-   4-(2-hydroxy-3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propoxy)benzonitrile    (m/z=452.5);-   4-({3-[7-(cyclopropylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propyl}amino)benzonitrile    (m/z=341.5);-   4-[(3-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)amino]benzonitrile    (m/z=463.5);-   4-[(3-{7-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)amino]benzonitrile    (m/z=412.5);-   4-[(3-{7-[3-(4-acetyl-1-piperazinyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile    (m/z=455.6);-   2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-N-isopropylacetamide    (m/z=386.5);-   4-[(3-{7-[3-(ethylsulfonyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-propyl)amino]benzonitrile    (m/z=421.5);-   4-[(3-{7-[2-(2-methoxyethoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)amino]benzonitrile    (m/z=389.5);-   4-({3-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile    (m/z=395.5);-   4-[(3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile    (m/z=435.5);-   4-{2-[7-(cyclopropylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethoxy}benzonitrile    (m/z=328.4);-   4-(2-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile    (m/z=450.5);-   4-(2-{7-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethoxy)benzonitrile    (m/z=399.5);-   4-(2-{7-[3-(4-acetyl-1-piperazinyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethoxy)benzonitrile    (m/z=442.5);-   2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-N-isopropylacetamide    (m/z=373.5);-   4-(2-{7-[3-(ethylsulfonyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethoxy)benzonitrile    (m/z=408.5);-   4-(2-{7-[2-(2-methoxyethoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile    (m/z=376.5);-   4-{2-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}-benzonitrile    (m/z=382.5);-   4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}sulfonyl)benzonitrile    (m/z=434.5);-   4-({3-[7-(cyclopropylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propyl}sulfonyl)benzonitrile    (m/z=390.5);-   4-[(3-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1    n]non-3-yl}propyl)sulfonyl]benzonitrile (m/z=512.4);-   4-[(3-{7-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)sulfonyl]benzonitrile    (m/z=461.4);-   4-[(3-{7-[3-(4-acetyl-1-piperazinyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)sulfonyl]benzonitrile    (m/z=504.5);-   2-(7-{3-[(4-cyanophenyl)sulfonyl]propyl}-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)-N-isopropylacetamide    (m/z=435.5);-   4-[(3-{7-[3-(ethylsulfonyl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-propyl)sulfonyl]benzonitrile    (m/z=470.4);-   4-[(3-{7-[2-(2-methoxyethoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)sulfonyl]benzonitrile    (m/z=438.5),-   4-({3-[7-(4-fluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-sulfonyl)benzonitrile    (m/z=444.4);-   4-[(3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)sulfonyl]benzonitrile    (m/z=484.4);-   4-[(3-{7-[2-(4-fluorophenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile    (m/z=423.4);-   4-(2-{7-[2-(4-fluorophenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile    (m/z=410.4);-   4-{2-[7-(tetrahydro-2H-pyran-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethoxy]benzonitrile    (m/z=372.4);-   4-(3-{7-[2-(4-fluorophenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-2-hydroxypropoxy)benzonitrile    (m/z=440.4);-   4-{2-hydroxy-3-[7-(tetrahydro-2H-pyran-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propoxy}benzonitrile    (m/z=402.4);-   4-({3-[7-(2-fluoro-3,3-dimethylbutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile    (m/z 389.3);-   4-({3-[7-(2-hydroxy-3,3-dimethylbutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile    (m/z=387.0);-   4-({3-[7-(3,3-dimethylbutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propyl}amino)benzonitrile    (m/z=371.01);-   4-({3-[7-(2-oxopropyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile    (m/z=342.92);-   4-(2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile    (m/z=431.9);-   4-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethoxy)benzonitrile    (m/z=418.9);-   4-(2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)benzonitrile    (m/z=402.9);-   4-{4-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-butyl}benzonitrile    (m/z=383.9);-   4-{2-[7-(2-phenoxyethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}-benzonitrile    (m/z=393.9);-   2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-N,N-diethylacetamide    (m/z=387.0);-   4-[(3-{7-[4-(4-fluorophenyl)-4-oxobutyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile    (m/z=450.9);-   4-({7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-methyl)benzonitrile    (m/z=401.9);-   4-{2-[7-(2,4-difluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethoxy}benzonitrile    (m/z=400.0);-   4-[(3-{7-[4-(difluoromethoxy)benzyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)amino]benzonitrile    (m/z=442.9);-   4-[(3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-propyl)amino]benzonitrile    (m/z=379.9);-   4-[(3-{7-[3-(4-bromophenyl)-3-oxopropyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propyl)amino]benzonitrile    (m/z=496.8);-   4-{2-[7-(2,2-difluoroethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethoxy}-benzonitrile    (m/z=337.8);-   4-({3-[7-(2-phenoxyethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile    (m/z=407.4);-   4-(2-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethoxy)benzonitrile    (m/z=367.4);-   4-[((2S)-3-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-2-hydroxypropyl)oxy]benzonitrile;-   4-[((2S)-2-hydroxy-3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)oxy]benzonitrile    (m/z=397.4);-   4-{2-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-ethoxy}isophthalonitrile    (m/z=397.4);-   4-(2-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethoxy)isophthalonitrile    (m/z=447.4);-   4-(2-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethoxy)isophthalonitrile    (m/z=392.4);-   tert-butyl    2-{7-[2-(2,4-dicyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethylcarbamate    (m/z=442.4);-   4-({(2S)-2-amino-3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]propyl}oxy)benzonitrile    (m/z=401.0);-   4-[((2S)-2-amino-3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)oxy]benzonitrile    (m/z=451.0);-   4-{3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propoxy}benzonitrile    (m/z=386.4);-   4-(3-{7-[2-(4-fluorophenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propoxy)benzonitrile    (m/z=424.4);-   4-(3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-propoxy)benzonitrile    (m/z=381.4);-   4-(4-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-butyl)benzonitrile    (m/z=379.4);-   4-{[(2S)-3-(7-{2-[4-(tert-butoxy)phenoxy]ethyl}-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl)-2-hydroxypropyl]oxy}benzonitrile    (m/z=496.6);-   4-[((2S)-3-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-2-hydroxypropyl)oxy]benzonitrile    (m/z=426.5);-   4-{3-[7-(imidazo[1,2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]propoxy}benzonitrile    (m/z=418.5);-   4-{3-[7-(2-phenoxyethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propoxy}-benzonitrile    (m/z=408.5);-   4-(3-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propoxy)benzonitrile    (m/z=410.5);-   4-({3-[7-(imidazo[1,2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]propyl}amino)benzonitrile    (m/z=417.5);-   4-({3-[7-(2,4-difluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propyl}amino)benzonitrile    (m/z=413.5);-   4-{[3-(7-{2-[4-(tert-butoxy)phenoxy]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)propyl]amino}benzonitrile    (m/z=479.6);-   4-{2-[7-(imidazo[1,2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]ethoxy}benzonitrile    (m/z=404.5);-   tert-butyl    2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate    (m/z=417.5);-   4-{[3-(7-{2-[4-(tert-butoxy)phenoxy]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)propyl]sulfonyl}benzonitrile    (m/z=528.5);-   4-[(3-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}propyl)sulfonyl]benzonitrile    (m/z=458.5);-   4-({3-[7-(2,4-difluorobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-propyl}sulfonyl)benzonitrile    (m/z=462.0);-   4-{2-[7-(imidazo[1,2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]ethoxy}isophthalonitrile    (m/z=429.0);-   4-[2-(7-{2-[4-(tert-butoxy)phenoxy]ethyl}-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl)ethoxy]isophthalonitrile    (m/z=491.6);-   4-(2-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethoxy)isophthalonitrile    (m/z=421.5);-   4-(4-{7-[2-(1H-imidazol-4-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}butyl)benzonitrile    (m/z=380.1);-   4-{4-[7-(imidazo[1,2-a]pyridin-2-ylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]butyl}benzonitrile    (m/z=416.5);-   4-{4-[7-(2-phenoxyethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]butyl}-benzonitrile    (m/z=406.5);-   4-(4-{7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}butyl)benzonitrile    (m/z=408.6);-   4-[3-(7-{2-oxo-2-[4-(1-pyrrolidinyl)phenyl]ethyl}-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl)propoxy]benzonitrile    (m/z=475);-   4-(3-{7-[2-(4-hydroxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propoxy)benzonitrile    (m/z=422),-   4-(3-{7-[2-(4-methylphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propoxy)benzonitrile    (m/z=420);-   4-(3-{7-[2-(4-methoxyphenyl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}propoxy)benzonitrile    (m/z=436);-   4-(3-{7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propoxy)benzonitrile    (m/z=464);-   4-(2-{7-[2-(2,6    dimethylphenoxy)-1-methylethyl]-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl}ethoxy)benzonitrile    (m/z=436);-   4-(3-{7-[2-oxo-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propoxy)benzonitrile    (m/z=477);-   tert-butyl    2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate    (m/z=431);-   N-(tert-butyl)-N′-(2-{7-[3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)urea    (m/z=430);-   tert-butyl    2-({7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}methyl)-1-pyrrolidinecarboxylate    (m/z=457);-   4-{[3-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}-benzonitrile    (m/z=377);-   4-[(3-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)amino]benzonitrile    (m/z=445);-   tert-butyl    2-{7-[2-(4-nitrophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate    (m/z=437);-   tert-butyl    2-[7-(2-{4-[(methylsulfonyl)amino]phenoxy}ethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethylcarbamate;-   tert-butyl    2-{7-[2-(4-aminophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate;-   4-({3-[7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}-amino)benzonitrile;    and-   4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzamide.

Example 13

Title compounds of the above Examples were tested in Test A above andwere found to exhibit D₁₀ values of more than 6.0.

Abbreviations

-   Ac=acetyl-   API=atmospheric pressure ionisation (in relation to MS)-   aq.=aqueous-   br=broad (in relation to NMR)-   Bt=benzotriazole-   t-BuOH=tert-butanol-   CI=chemical ionisation (in relation to MS)-   mCPBA=meta-chloroperoxybenzoic acid-   d=doublet (in relation to NMR)-   DBU=diazabicyclo[5.4.0]undec-7-ene-   DCM=dichloromethane-   dd=doublet of doublets (in relation to NMR)-   DMAP=4-dimethylaminopyridine-   DMF=N,N-diinethylformamide-   DMSO=dimethylsulfoxide-   EDC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide-   Et=ethyl-   EtOAc=ethyl acetate-   eq.=equivalents-   ES=electrospray (in relation to MS)-   FAB=fast atom bombardment (in relation to MS)-   h=hour(s)-   HCl=hydrochloric acid-   HEPES=4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-   HPLC=high performance liquid chromatography-   IMS=industrial methylated spirits-   IPA=iso-propyl alcohol (propan-2-ol)-   m=multiplet (in relation to NMR)-   Me=methyl-   MeCN=acetonitrile-   MeOH=methanol-   min.=minute(s)-   m.p.=melting point-   MS=mass spectroscopy-   NADPH=nicotinamide adenine dinucleotide phosphate, reduced form-   OAc=acetate-   Pd/C=palladium on carbon-   q=quartet (in relation to NMR)-   rt=room temperature-   s=singlet (in relation to NMR)-   t=triplet (in relation to NMR)-   TEA=triethylamine-   THF=tetrahydrofuran-   tlc=thin layer chromatography

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

1. A pharmaceutical composition comprising tert-butyl2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3yl}ethylcarbamateor a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.